An Overview On 5reductase Inhibitors

Steroids 75 (2010) 109153
Contents lists available at ScienceDirect

Steroids
j our nal homepage: www. el sevi er . com/ l ocat e/ st er oi ds
Review
An overview on 5-reductase inhibitors
Saurabh Aggarwal
a
, Suresh Thareja
a
, Abhilasha Verma
a
, Tilak Raj Bhardwaj
a,b
, Manoj Kumar
a,
a
University Institute of Pharmaceutical Sciences, Panjab University, Chandigarh 160014, India
b
I. S. F College of Pharmacy, Ferozepur Road, Moga, Punjab 142001, India
a r t i c l e i n f o
Article history:
Received 13 July 2009
Received in revised form 9 October 2009
Accepted 20 October 2009
Available online 30 October 2009
Keywords:
5-Reductase inhibitors
Androgens
Azasteroids
Testosterone
BPH
5-Dihydrotestosterone
a b s t r a c t
Benign prostatic hyperplasia (BPH) is the noncancerous proliferation of the prostate gland associated
with benign prostatic obstruction and lower urinary tract symptoms (LUTS) such as frequency, hesitancy,
urgency, etc. Its prevalence increases withage affecting around 70%by the age of 70 years. Highactivity of
5-reductase enzyme in humans results in excessive dihydrotestosterone levels in peripheral tissues and
hence suppression of androgen action by 5-reductase inhibitors is a logical treatment for BPH as they
inhibit the conversion of testosterone to dihydrotestosterone. Finasteride (13) was the rst steroidal 5-
reductase inhibitor approved by U.S. Food and Drug Administration (USFDA). In human it decreases the
prostatic DHT level by 7090% and reduces the prostatic size. Dutasteride (27) another related analogue
has beenapprovedin2002. UnlikeFinasteride, Dutasterideis acompetitiveinhibitor of both5-reductase
type I and type II isozymes, reduced DHT levels >90% following 1 year of oral administration. A number
of classes of non-steroidal inhibitors of 5-reductase have also been synthesized generally by removing
one or more rings fromthe azasteroidal structure or by an early non-steroidal lead (ONO-3805) (261). In
this review all categories of inhibitors of 5-reductase have been covered.
2009 Elsevier Inc. All rights reserved.
Contents
1. Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 110
2. Enzyme 5-reductase. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 110
3. Steroidal 5-reductase inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 111
4. 2- and 3-Azasteroids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 111
5. 4-Azasteroids. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 112
6. 6-Azasteroids. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 121
7. 7-Azasteroids. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 124
8. 8-Azasteroids. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 124
9. 9-Azasteroids. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 124
10. 19-Nor-10-azasteroids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 124
11. 11-, 12a-, 13-Azasteroids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 125
12. 15- and 16-Azasteroids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 125
13. 17- and 17a-Aza-D-homosteroids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 125
14. Diazasteroids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 125
15. 11,13,15-Triazasteroids. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 126
16. B,D-Dihomo-azasteroids. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 126
17. Des-AB-azasteroids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 126
18. Steroidal 3-carboxylic/phosphonic/phosphinic acids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 127
19. Diazoketone steroids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 128
20. 4-Substituted steroids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 128
21. Steroidal oximes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 129
22. Steroidal tetrahydrooxazin-2-ones. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 129
Corresponding author. Tel.: +91 172 2534115; fax: +91 172 2534112.
E-mail addresses: aggarwalsau@gmail.com (S. Aggarwal), manoj uips@pu.ac.in (M. Kumar).
0039-128X/$ see front matter 2009 Elsevier Inc. All rights reserved.
doi:10.1016/j.steroids.2009.10.005
110 S. Aggarwal et al. / Steroids 75 (2010) 109153
23. 16-Substituted steroids. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 130
24. 6-Methylene steroidal derivatives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 130
25. Seco steroids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 131
26. Derivatives of natural substrate: pregnane . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 131
27. Non-steroidal 5-reductase inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 135
28. Mimics of 4-azasteroids: benzo[f]quinolinones. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 135
29. Pyridones, quinolinones and piperidines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 136
30. Mimics of 6-azasteroids: benzo[c] quinolinones. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 139
31. Mimics of 10-azasteroids: benzo[c] quinolizinones . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 139
32. Non-steroidal aryl acids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 141
33. Bisubstrate inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 146
34. Miscellaneous non-steroidal inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 147
35. Conclusion and future ahead . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 149
Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 149
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 149
1. Introduction
Benign prostatic hyperplasia (BPH) is the noncancerous growth
of the prostate gland resulting due to over-proliferation of the
stromal and glandular elements of the prostate [1]. It is caused
due to the augmented levels of the androgen dihydrotestosterone
(DHT). In BPH, microscopic foci within specic regions of the
prostate grows to formmacroscopic nodules which eventually dis-
place the normal prostatic tissue and results into the uretheral
compression. This compression resulting due to increased cell pro-
liferation and/or impaired apoptosis causes physical enlargement
of the prostate gland and is referred to as static component. In
addition dynamic component involves sympathetic nerve stim-
ulation causing contraction of prostatic and uretheral smooth
muscle which results into outow obstruction [2]. Despite several
hypotheses the molecular trigger for BPH remains unknown [3].
The incidence of BPH is about 70% at 70 years of age and becomes
nearly universal with advancing age. Clinically, BPH causes a con-
stellation of symptoms known as lower urinary tract symptoms
(LUTS). The hallmarks of the LUTS include frequency, hesitancy,
urgency, nocturia, slow urinary stream and incomplete emptying
[4]. Earlier the choice of treatment in BPH was watchful waiting,
transurethral resection of the prostate (TURP) or open prostate-
ctomy but due to the invasive nature and potential side effects
manymedical therapies have emergedinvolving the suppressionof
androgenstimulationof prostatic growth[5]. These therapies delay
or eliminate the requirement of surgery. 5-Reductase enzyme
has emerged as a target for the pharmaceutical treatment of BPH
as abnormally high activity of the enzyme in humans results in
excessive DHT levels in peripheral tissues and hence suppression
of androgenactionby 5-reductase inhibitors is a logical treatment
for BPH [6]. A large number of molecules have been synthesized as
potential 5-reductase inhibitors over the years. Several analogues
may also act as androgen receptor antagonists by preventing the
natural ligands of the androgenreceptor suchas testosterone (T) (1)
andDHT(2) frombinding tothe receptor. Combinationof these two
categories of inhibitors may provide effective androgen receptor
blockage without undesirable side effects of castrate testosterone
levels onmuscleandbonemass, energylevel andlibidowhichareof
particular concern [7]. Some earlier reports have been there cover-
ing various aspects of 5-reductase enzyme and inhibitors [810]
but a comprehensive review of each category and structural fea-
tures required for 5-reductase inhibitory activity were missing.
This reviewis an attempt to cover all categories of inhibitors of 5-
reductase with an aim to list the most potent compounds of each
category along with the special structural requirements that led
to 5-reductase inhibitory activity and in vitro data obtained from
the evaluation of steroidal and non-steroidal compounds that have
been tested as inhibitors of 5-reductase. In particular IC
50
and K
i
values for relevant compounds have been compared according to
the molecular class. The values given are not comparable across
the studies and in each comparison a standard taken in the study
is mentioned.
2. Enzyme 5-reductase
A signicant correlation between the androgens and prostate is
well known. Testicular androgens constitute the most important
mitogenic factor in vivo for the prostate [11]. Normal circulating
levels of androgens are required for the maintenance of structural
function, growth and integrity of the prostate tissue. However,
androgens have no direct effect on prostatic epithelial cells in
culture [12]. Androgens enhance the production of many growth
factors in the prostate tissue in vivo through a complex cell to
cell interaction involving both epithelial and stromal prostatic cells
[13]. Androgen signalling cascade involves the synthesis of T (1) in
testes andadrenal glands whichgets peripherally convertedtoDHT
(2). DHT formed gets transferred to the target tissues and binds to
the target receptor withconsequent modulationof gene expression
[14]. Both T and DHT bind to and activate the androgen receptor
(AR), but DHT shows a higher afnity leading to different kinetic
processes. DHT dissociates fromARproteinmuchmore slowly than
its precursor. Therefore, at a given time ARs are occupied by DHT
much more than by testosterone. T is converted to DHT by a steroid
5-reductase enzyme (3-oxo-steroid-4-ene dehydrogenase {E.C.
1.3.99.5}) which is a systemof two membrane bound nicotinamide
dinucleotide phosphate (NADPH) dependent enzymes at the level
of prostatic stromal and basal cells. This has led to the develop-
ment of steroidal andnon-steroidal 5-reductase inhibitors as they
inhibit the conversion of T (1) to DHT (2) as shown in Fig. 1 [1517].
Thus 5-reductase dictates the cellular availability of DHT to pro-
static epithelial cells and consequently modulates its growth.
The proposed chemical mechanismof T (1) reduction to DHT (2)
by 5-reductase catalysis involves the formation of a binary com-
plex betweenthe enzyme andNADPH, followedby the formationof
a ternary complex withthe substrate T. Adelocalizedcarbocationis
Fig. 1. Site of action of 5-reductase inhibitors.
S. Aggarwal et al. / Steroids 75 (2010) 109153 111
Fig. 2. 5-Reduction of 3-keto-
4
steroids.
formed due to the activation of the enone systemby a strong inter-
action with an electrophilic residue (E
+
) present in the active site.
Enolateof DHTis formedbythedirect hydridetransfer fromNADPH
to the face of the delocalized carbocation leading to a selective
reduction at C-5. This enolate which is coordinated with NADP
+
on
the face, is attacked by a proton on the -face at C-4 giving the
ternary complex E-NADP
+
-DHT. Binary NADP
+
enzyme complex
is formed after departure of DHT and nally the release of NADP
+
leaves the free enzyme for further catalytic cycles. Three differ-
ent types of inhibitors could be conceived according to the kinetic
mechanism of testosterone reduction: type A inhibitors which are
competitive with the cofactor (NADPH) and the substrate (T) and
interact with the free enzyme; type B inhibitors which are compet-
itive with the substrate and t the enzymeNADPH complex, and
type Cinhibitors whichts the enzymeNADP
+
complex exhibiting
uncompetitive mechanism versus the substrate [8,18].
More potent inhibitors of steroid 5-reductase have been found
among the transition state analogues as molecules mimicking the
transitionstateof theenzymatic processes exhibit agreater binding
to the enzyme and hence produce greater inhibition. The enzyme
5-reductase binds the 3-keto-
4
steroids in such a way that the
carbonyl group is brought into vicinity of a positively charged
centre on the enzyme whereby the conjugated ketone becomes
activated as shown in Fig. 2.
A hydride ion can then be transferred from the coenzyme
NADPH to the 5-position of the steroid. The resulting enolate is
protonated at the axial 4-position by the solvent and the product
is released. This evidence for protonation was based on the model
studies withthePenicilliumdecumbens 5-reductaseenzyme[19].
Modern methods of molecular biology had assisted in identi-
fying two types of 5-reductase enzyme: type I and type II from
human and rat prostatic complimentary deoxyribonucleic acid
(cDNA) libraries and the structures of both genes were elucidated
at the beginning of this decade [20,21]. The type I enzyme is not the
major species expressedinthe prostate andis present mainly inthe
hair follicles andperipheral skinwhereas typeII 5-reductaseis the
major isozyme in genital tissues and a deletion in the gene leads
to male pseudohermaphroditism [22,23]. Type I enzyme is consti-
tutively expressed in the brain and in adulthood appears mainly
localized in the myelin membranes and has a catabolic rather than
an activating role in the brain while type II enzyme is transiently
expressed in the prenatal period and in males its expression is
controlledby androgens andappears tobe connedinthe hypotha-
lamus and in the hippocampus after stress hence type II enzyme
might participate in the perinatal differentiation of brain towards
a male pattern [24].
The two isozymes differ in the constitution of amino acids as
well as molecular weight. The type I isozymes is active at pH 69
while type II is active at pH 5.5. The two isozymes also differ in
the location of the gene structure while type I is located at 5p15
while type II is located at 2p22 although they had same gene struc-
ture [8,25]. The comparison of the properties of two isozymes is
summarized in the Table 1:
More recently with the development of genome-wide gene
expression prole analyses a third type of 5-reductase enzyme
(type III) has been identied in hormone-refractory prostate can-
cer cells (HRPC) [26]. This enzyme also converts T to DHT in HRPC
cells in a similar way to type I enzyme and was found to be active
at pH6.9 [27]. Type III isozyme has been recognized as a ubiquitous
enzyme in mammals. Northern blot and real time RT-PCR analyses
have identied this enzyme in both androgen and non-androgen
target human tissues such as pancreas, brain, prostate cancer cell
lines, skin and adipose tissues [28].
Based on their structure 5-reductase inhibitors are discussed
below as steroidal and non-steroidal inhibitors.
3. Steroidal 5-reductase inhibitors
As the only information available about the 5-reductase
isozymes is their primary sequence estimated from c-DNAs the
design of novel inhibitors is affected. Due to the unstable nature
of enzyme during purication its crystal structure is not known.
The rst inhibitors have been therefore designed by modifying the
structure of natural substrates, including the substitution of one
carbon atom of the rings of the steroids by a heteroatom such as
nitrogen thereby forming azasteroids. Singh and coworkers [29,30]
as well as other groups have published comprehensive reviews on
biological activityof azasteroids [31]. Azasteroidal compounds hav-
ing nitrogens at various positions have also been covered in this
review. However, their 5-reductase inhibitory activity has either
not been done or they are devoid of activity. Some azasteroids have
been found to be 5-reductase inhibitors. In the following section
azasteroidal inhibitors have been discussed depending upon the
positionof nitrogeninthesteroidal nucleus, i.e. nuclear azasteroids.
4. 2- and 3-Azasteroids
Although some of the 3-azasteroids were synthesized by
Doorenbos and Wu [32] and Mazur [33] in the early 1960s but
Anderson and Liao in 1968 reported for the rst time that steroidal
N-oxido-3-aza-1,3,5(10)-triene is a good inhibitor of enzyme 5-
reductase [34]. Haffner in 1994, reported the synthesis of some
novel 3-pyridyl-N-oxide steroids (3 and 4) [35] which mimic the
enolate or enol like transition state of the enzymesubstrate com-
plex.
Table 1
Comparison of properties of 5-reductase isozymes.
a
Properties Type I 5-reductase Type II 5-reductase
Size 259 amino acids 245 amino acids
Molecular weight 29,462Da 27,000Da
Optimal pH 68.5 5.05.5
Biochemical properties Hydrophobic Hydrophobic
Gene location SRD5A1, 5p15 SRD5A2, 2p23
Gene properties 5 exons, 4 introns 5 exons, 4 introns
In vitro inhibition by Finasteride K
i
300nM K
i
=35nM
Localization (in tissues) Sebaceous glands of the skin, sweat glands, dermal papilla cells
broblasts from all areas, epidermal keratinocytes, follicular
keratinocytes
Prostate, genital skin, epididymis, seminal
vesicles
Selectivity to the inhibitors Inhibitors with 4-methyl-4-aza functionality are very potent 4-Aza, 6-aza and charged 3-substituents
derivatives are highly selective
a
Ref. Li et al. [8].
N-Oxidesteroids (3) and(4) wereassayedagainst bothtypeI and
type II 5-reductase and proved to be potent inhibitors of type II
5-reductase with the K
i
(M) being 0.031 and 0.104, respectively.
In 2003, Robinson et al. reported the synthesis of various 2- and
3-azasteroidal derivatives (510) as effective and stable transition
state 5-reductase inhibitors [36].
All the synthesised 2- and 3-azasteroids (510) were evaluated
for human5-reductase inhibition. Amines (6and10) showedpoor
inhibitory activity against both type I and type II isozymes whereas
lactams (5 and 9) displayed only marginal improvement against
type II isozymes. However, nitrones (7 and 8) showed signicant
enhancement in biological activity.
5. 4-Azasteroids
4-Azasteroids is one of the extensively studied and clinically
used classes of azasteroidal 5-reductase inhibitors. Voigt et al. in
1970, screened a large number of steroids including 23 steroidal
hormones for their ability to inhibit the conversionof T (1) into DHT
(2) by a crude cell free enzyme system isolated from rat ventral
prostate [37]. In 1973, series of effective 5-reductase inhibitors
were synthesized and evaluated. From the studies it was estab-
lished that the key structural requirements for the 5-reductase
inhibitory activity were presence of 4-en-3-one function and 17-
side chain having one or more oxygen functionalities. Molecules
possessing these features act as competitive inhibitors of testos-
terone 5-reductase, therefore, all of them could be regarded as a
substrate of the enzyme 4-en-3-one steroids [38]. 4-Androsten-3-
one-17-carboxylic acid (11) was identied as a potent inhibitor of
5-reductase.
It has been reported to be a competitive inhibitor of the enzyme
and showed 87.7% inhibition for the microsomal enzyme of human
skin. None of the compounds from this series could be shown
to interfere with in vivo conversion of the dihydrotestosterone,
because of their rapidconversionintothe inactive 4,5-dihydroform
by the enzyme.
Fig. 3. Basic SAR of 4-azasteroids.
In search for a nonreducible inhibitor of 5-reductase, Merck
and Co. in 1980 reported series of 4-azasteroids where C-4 of 3-
oxo-5-steroids was replaced by nitrogen. The studies showed
that there was not only an increase in the 5-reductase inhibitory
activity but also retention of the in vivo activity [39,40]. Therefore,
azasteroids were designed to mimic the putative enzyme-bound
enolate intermediate by incorporating sp
2
-hybridized center at C-
3 and C-4. Thus a lactamwas introduced inthe ring Aof the steroids
tomimic the enol transitionstate of the enzymeNADPHsubstrate
(E.NADPH.S) complex. Substitution at C-17 has been found to
enhance potency by binding to a lipophilic pocket on the enzyme.
These competitive inhibitors strongly interact with the enzyme at
the active site andonother handunlike the substrate cannot be fur-
ther reduced to 5-metabolites thus have in vivo inhibitory activity
[41]. The steroidal pharmacophore provides ananchor betweenthe
key A-ring lactamand the C-17 substituent while the former acts as
a transition state mimic of intermediate enolate, the latter signi-
cantly enhances potency via binding at a pocket largely lipophilic in
nature. The key 4-aza-3-oxo-5-androstane pharmacophore and
the basic structure activity relationship (SAR) is outlined below
(Fig. 3) [42,43].
Taking into consideration that substitution at C-17- could dra-
matically affect the potency; a large number of modications were
carried out to nd potent inhibitors [4446].
4-MA {17-N,N-diethylcarbamoyl-4-methyl-4-aza-5-
androstan-3-one} (12) was found to be a potent dual inhibitor
of both human 5-reductase isozymes having IC
50
value of
1.9nM against human 5-reductase II and 1.7nM against human
5-reductase I, however, it was withdrawn from the clinical
developments due to hepatic toxicity and lack of selectivity over
3-hydroxy steroid dehydrogenase enzyme [4749]. Out of the
series its unsaturated analogue 17-(N-tert-butylcarbamoyl)-4-
aza-5-androst-1-en-3-one, MK-906, Finasteride (13) was found
to be the best and extensively studied. Finasteride (13) was a
potent inhibitor of 5-reductase type II with only weak in vitro
activity versus 5-reductase type I having IC
50
value of 9.4 and
410nM, respectively. At clinical dose, 5mg/day, it caused 6580%
lowering of plasma DHT levels [50]. Finasteride (13) was the
rst drug to be approved in U.S. for BPH. Long-term studies have
demonstrated that there is a sustained improvement in BPH
disease and reduction in the prostate specic antigen (PSA) level
[51].
It was reported by Merck as well as Glaxo in 1996 that Finas-
teride (13) and close analogues are mechanism-based inactivators
of 5-reductase II. Although it is accepted as an alternate substrate
and is ultimately reduced to dihydronasteride (15), this pro-
ceeds through an enzyme-bound NADP-dihydronasteride adduct.
Initially it was believed that Finasteride (13) act as a transition
state mimic whereby conrmation of the A-ring lactam closely
mimics the enol form of transition state of 5-reduced testos-
terone but now it is understood that the most likely cause of
the slow offset inhibition is rate-limiting hydride transfer from
NADPH to the
1
-double bond of Finasteride (13). In the case of
the 1,2-ene-containing Finasteride (13), reduction of C1 enables
the nucleophilic attack of C2 on the nicotinamide C4. This aber-
rant reduction results in the formation of lactam enolate which
is not positioned for efcient protonation by the enzyme. Instead
the enolate is trapped by the electrophilic pyridiniumcation of the
NADP, yielding a covalent adduct to the cofactor and to the pro-
tein (Fig. 4). This dihydronasterideNADP adduct is a remarkably
potent bisubstrate analog inhibitor and it binds to the free enzyme
with a second-order rate constant equal to k
cat
/K
m
for turnover of
T (1) and has a dissociation constant K
i
110
13
M. Finasteride
(13) is also a mechanism-based inhibitor of the human skin (type
I) isozyme, but it is processed with a much smaller second-order
rate constant, k
i
/K
i
=310
3
M
1
s
1
, which attenuates its activ-
Fig. 4. Mechanism of Finasteride inhibition of 5-reductase.
Table 2
In vitro screening of compounds 2027 against type I and type II human steroid
5-reductase.
Compounds Human 5-reductase
type I, IC
50
(nM)
Human 5-reductase
type II, IC
50
(nM)
20 20 0.2
21 350 24.6
22 >1000 25.2
23 120.2 0.4
24 5.6 <0.1
25 14.0 <0.1
26 8.1 0.2
Dutasteride (27) 2.4 0.5
Finasteride (13) 52 <0.1
ity against this isozyme in vivo. Indeed, Merck has demonstrated
the presence of (14c) in the inhibited form of 5-reductase type I
[5254].
Weintraub et al. in 1985 reported 20-(hydroxymethyl)-4-
methyl-4-aza-2-oxa-5-pregnan-3-ones and their corresponding
3-thiones (1619). These compounds were tested in vitro for
inhibition of testosterone 5-reductase and were found to be
weak inhibitors with K
i
s in the 10
7
range. It was argued that
replacement of C-2 in the steroid nucleus by oxygen in the case
of 4-aza-3-oxo-steroids would convert it to a urethane (17) from
a lactam (16), respectively, thereby enhancing the polarity at C-3
carbonyl, and its afnity for the enzyme active site [55].
Table 3
In vitro screening of compounds 2833 against human and rat prostatic 5-
reductase.
Compounds Human 5-reductase,
IC
50
(nM)
Rat 5-reductase, IC
50
(nM)
28 41 83
29 212
Turosteride (30) 55 53
31 381 227
32 1218 1611
33 1553 1154
4-MA (12) 28 37
Bakshi et al. reported a series of 4-aza-3-oxo-5-androstene-
l7-N-aryl-carboxamides as dual inhibitors of human type I and
type II steroid 5-reductases [56]. Some of these compounds
were found to be potent inhibitors of both isozymes. Variation of
the C-17 amide substituent on the 4-aza-3-androstane skeleton
has resulted into a fruitful search of the potent dual azasteroid
inhibitors (2026).
Dutasteride (GG745), 17-N-{2,5-bis(triuoromethyl)-
phenyl)}-3-oxo-4-aza-5-androst-1-ene-17-carboxamide (27)
had emerged as the most potent dual inhibitor from this group
(Table 2) [57]. It has been approved by U.S. FDA in 2002, for the
symptomatic treatment of BPH [58,59]. Unlike Finasteride (13),
Dutasteride (27) is a competitive inhibitor of both 5-reductase
type I and 5-reductase type II isozymes, reduced dihydrotestos-
terone levels >90% following one year oral administration [60]. It
is also a time dependent inhibitor as Finasteride (13) and it forms
a stable complex with a slow rate of dissociation constant and
does not bind to the androgen receptor [61]. By reducing DHT
level, it reduces the size of enlarged prostate, so improving the
urinary owrate. It is about 60 times more potent than Finasteride
(13) and has been shown to decrease the risk of acute urinary
retention and BPH related surgery [6264]. This greater degree of
suppression of serum DHT has been found to correlate with the
intraprostatic DHT suppression. Dual inhibition of 5-reductase is
more benecial than selective type II inhibition as dual inhibition
does not allow the escape of DHT which can formed through type
I mediated synthesis thus providing greater efcacy as DHT levels
are suppressed to a great extent. Long-term studies have shown
that Dutasteride (27) a dual inhibitor is well tolerated during daily
use for up to 2 years. It had a tolerability prole comparable to that
of placebo with the exception of a modestly elevated incidence
of impotence and decreased libido compared with placebo. Also
Dutasteride didnot clinically signicantly impact bone metabolism
markers, bone mineral density or lipid levels [65].
In a programme aimed at searching for novel 5-reductase
inhibitors a series of C-17-acylurea-substituted 4-azasteroids
(2833) (Table 3) were synthesized by Di Salle et al. in early 1990s
exploiting the tolerance of functionality at this position. Signi-
cantly greater potency was found with the derivative containing
C-4 methyl group and a saturated A-ring [66].
Table 4
In vitro screening of compounds 3843 against type I and type II human steroid
5-reductase.
Compounds IC
50
(nM) or % inhibition at 100nM (given in parenthesis)
Human 5-reductase
type I (transfected 293
cells)
Human 5-reductase
type II (transfected
SW-13 cells)
38 27.3 3.4 (203.1)
39 5.3 1.1 (46.31.3)
40 24.2 1 (4.90.2)
41 1.3 0.64 (56.34.5)
42 31.5 6.0 (48.74.2)
43 11.5 1.9 (39.70.4)
Finasteride (13) 262 43.2 8.50.4
Table 5
In vitro screening of compounds 4449 against type I and type II human 5-
reductase.
Compounds Type I, IC
50
(nM) Type II, IC
50
(nM)
44 3.05 0.296 >100
45 0.91 0.236 >100
46 2.19 0.476 >100
47 2.35 0.421 >100
48 9.57 1.745 141.11
49 16.9 3.911 18.41.541
Finasteride (13) 26.3 4.784 4.530.96
Table 6
reductase.
50
(nM) Type II, IC
50
(nM)
50 1.77 0.343 1000>IC
50
>100
51 2.42 0.409 1000
52 2.93 2.158 3.751.977
53 10.5 2.739 582
54 5.44 1.067 1000>IC
50
>100
Finasteride (13) 26.3 4.784 4.530.96
One of the most potent compound of this group, Turosteride
(30), a close analogue of 4-MA (12), but unlike 4-MA was found
to be devoid of binding at the rat androgen receptor and a weak
inhibitor of 3-hydroxy steroid dehydrogenase [67].
Other azasteroids which retained 5-reductase inhibitory
activity are 2-substituted (34), A-homo- (35) and 19-nor- (36)
analogues [41].
Observation that selectivity of inhibitors can be increased
against type I isozyme by making correct choice of hydrophobic
substituent at C-17 position led to development of various 17-(N-
ureylene-N,N
-disubstituted)-4-methyl-4-aza-3-one 5-reductase
derivatives (Table 4) (3843) as 5-reductase inhibitors as they
have potent selectivity against 5-reductase type I enzyme. Aza-
steroids with N-cyclopropyl ring exhibit potent inhibitory activity
against type I 5-reductase. Increase in the chain length from N
-
ethyl to N
-butyl the compound showed strong inhibitory activity

while branching of alkyl chain decreased potency of compounds
and introduction of 1,2-double bond signicantly reduced the
activity. Replacement of N
-alkyl chain with phenyl moiety gave

the most active compound (41) of the series [68].
From the studies that 17-carboxamides at C-17 position
have pronounced activity of 5-reductase and possess andro-
gen receptor activities, a number of 17-(N-alkyl/aryl formamido)
(4449) and 17-[(N-alkyl/aryl)alkyl)aryl amido]-3-oxo-4-aza-
5-steroids (5054) were prepared from 17-hydroxy-4-aza-
steroids and were evaluated as 5-reductase inhibitors by Li et al.
(Tables 5 and 6). Structure activity relationship indicated that 5-
reductase type I enzyme has preference for N-substituted linear
alkyl side chain of 45 carbon atoms. N-Amyl substituted 17-
formamide(45) was foundtobeoneof themost promisinginhibitor
of 5-reductase type I while N-heptyl (48) andN-octyl (49) showed
dual inhibition of both isozymes of 5-reductase (Table 5).
Similarly in series of 17-[(N-alkyl/aryl) alkyl) arylamido]
derivatives (Table 6) exhibited highly potent inhibitory activity for
human 5-reductase type I [69].
Various 7-substituted derivatives have also been prepared.
Preliminary screening of the compounds as inhibitors of 5-
reductase from human scalp and prostate revealed that the
presence of 7-methyl substitution in ring B, presence of choles-
terol type side chain at C-17 and ketone functionalities at C-3
in 4-azasteroids resulted in potent selective inhibitor against 5-
reductase type I [70].
4,7-Dimethyl-4-aza-5-cholestan-3-one (MK 386) (61)
emerged as one of the most potent inhibitor of type I 5-reductase
Table 7
reductase.
Compounds IC
50
(nM)
Type 1 Type 2
55 1.7 218
56 5.7 330
57 1.6 298
58 2.0 125
59 0.6 147
60 8.4 5.4
MK-386 (61) 0.9 154
Table 8
In vitro screening of compound 62 against human and rat 5-reductase inhibition.
a
Compounds IC
50
(nM)
Human Rats
FCE 27837 (62) 51(3) 60(3)
Finasteride 51(6) 32(5)
a
Number of assays in parentheses.
(Table 7) [71].
During 1995, some 17-hydroxy-17-(-hydroxy/haloalkyn-
l
-yl)-4-methyl-4-aza-3-oxo-5-androst-1-ene-3-ones were syn-

thesised by Li et al. and their antiandrogenic activity was
reported [72]. Salle et al. have reported synthesis and 5-
reductase inhibitory properties of various 4-azasteroids withuoro
substituted 17 amidic side chains [73] and further investi-
gated FCE 27837 (N-[1,1,1-triuoro-2-oxobut-3-yl]-3-oxo-4-aza-
5-androst-1-ene-17-carboxamide) (62), for its endocrinological
properties in comparison with those of Finasteride (13) (Table 8)
[74].
Table 9
In vitro screening of compounds 6366 against human steroid 5-reductase.
Compounds Human 5-reductase inhibition K
i
(nM)
63 2.6
64 1.8
65 2.2
66 5.1
In order to have specic and dual inhibitors of 5-reductase
Labrie and associates synthesized several steroids having lactamin
ring A and substitution at 17 position. Several of the compounds
were found active (Tables 9 and 10) [75].
Table 10
Compounds Human 5-reductase inhibition K
i
(nM)
67 0.5
68 2.3
69 3.2
Table 11
Compounds Human 5-reductase, IC
50
(nM)
70 16
71 8
72 14
Panzeri et al. reported the syntheses of several 17-
substituted4-aza-5-androstan-3-one carboxamides withunsatu-
ration between C-1 and C-2 (7072). These were found to be highly
potent against human 5-reductase enzyme (Table 11) [76].
Table 12
In vitro screening of compound 73 against human steroid 5-reductase.
50
(nM) Type II, IC
50
(nM)
73 36 9 3.3 1.2
Finasteride (13) 470 41 8.5 1.2
Table 13
In vitro screening of compound 74 against rat and human steroid 5-reductase.
Compounds IC
50
(nM)
Rat prostate 5-reductase Human prostate 5-reductase
74 36 262
Finasteride (13) 11 18
In 1996, Giudici et al. reported the synthesis of FCE 28260
(73) [(22R,S)-N-(1,1,1-triuoro-2-phenylprop-2-yl)-3-oxo-4-aza-
5-androst-1-ene-17-carboxamide] (Table 12) as a potent dual
inhibitor of both 5-reductase isozymes and it was found to cause
74% reduction in the DHT levels [77].
CIBA-GEIGY Ltd. reported the synthesis of CGP53153
(N-(2-cyano-2-propyl)-3-oxo-4-aza-5-androst-1-ene-17-
carboxamide) (74) (Table 13), a novel inhibitor of 5-reductase
and structurally related to Finasteride (13) was found to be 10
times more potent than Finasteride in reducing prostate weight of
rat [78].
In 1996, Ishibashi et al. reported the synthesis of various
11-acetoxy, 11-hydroxy, 11-hydroxy and 11-oxo substituted
4-aza-5-androstane analogues (7579) with a diphenylmethyl-
carbamoyl moietyat C-17andtheir evaluation. Compounds withan
11-hydroxy or 11-oxo showed inhibitory activities comparable to
Finasteride (13). The 4-methyl 11-hydroxy-4-aza-5-androstane
derivative (77) was found to be most potent against rat and human
enzyme and more active than Finasteride (13) (Table 14) [79].
Table 14
Compounds Rat 5-reductase
%inhibition at
10
8
M
Human 5-reductase relative
inhibitory potency to MK-906
(MK-906=1)
75 50 0.55
76 74 1.6
77 74 2.9
78 39 <0.1
79 33 1.0
Finasteride (13) 28 1.0
Table 15
Compounds IC
50
(nM)
Type I Type II
80 13 0.2
81 420 20
82 30 210
83 120 50
84 410 15
85 5 11
Table 16
Compounds IC
50
(nM)
Type I Type II
86 30 210
87 6 10
88 2 7
89 6 20
Merck in 1997 reported the synthesis of several 4-aza 5-
androstan-3-one 17-(N-substituted carboxamides) (8085) as
potent human type II 5-reductase inhibitors. From the studies it
was indicated that the 17-amide N substituent included aromatic
residue potent dual inhibitors of type I and type II 5-reductase
were obtained (Table 15).
The addition of N
4
-methyl substituent in A-ring increases
human androgen receptor afnity while addition of unsaturation
to the A-ring (
1
) increased human androgen receptor binding.
The unsubstitutedcarbanilides inthe
1
-N
4
-methyl series showed
some selectivity for type I 5-reductase over type II enzyme.
Whereas addition of aryl substitution at the 2-position increased
type II 5-reductase binding, thus providing dual inhibitors with
excellent human androgen receptor binding. Compound (87) was
found to be the most potent inhibitor from this series (Table 16)
[80].
In 1998, Salle et al. reported synthesis of a novel compound PNU
157706 [N-(1,1,1,3,3,3-hexauorophenylpropyl)-3-oxo-4-aza-5-
androst-1-ene-17-carboxamide] (90) as a potent dual type I and
type II 5-reductase inhibitor. PNU 157706 (90) was found to
reduceprostateweight 16-foldthanFinasteride(13) whiletheED
50
values being 0.12 and 1.9mg/kg/day, respectively (Table 17) [81].
Fig. 5. SAR of 6-azasteroids.
In 2000, Lerner and coworkers reported the synthesis of
haptens 91(a,b) and 92(a,b) which belongs to 4-aza steroids.
The resulting 5-dihydrotestosterone was shown to be the more
potent intracellular hormone [82].
Table 17
In vitro screening of compound 90 against human steroid 5-reductase.
a
Compounds Type I Type II
90 3.9 0.1 1.8 0.3
Finasteride (13) 313 74 11.3 2.6
a
Results are the meanSE of 3 separate assays. Incubations were performed in
thepresenceof 3or 1M[
3
H] testosterone, for typeI or typeII isozyme, respectively.
Table 18
Compounds Type I 5-reductase,
IC
50
(nM)
Type II
5-reductase, IC
50
(nM)
94 750 1.5
95 180 2.3
96 51 9
97 97 2.1
98 40 3.9
99 1,300 5.7
100 14,000 1.8
101 3,500 3.4
Menzenbach et al. reported the synthesis of several 17-
methylene-4-azasteroids as inhibitors of 5-reductase. Azaestra-
none II (93) was found to be inhibitor of 5-reductase with
IC
50
=3410
10
(for prostate) and IC
50
=2510
10
(for seminal
vesicle) [83].
6. 6-Azasteroids
Glaxo was the rst to report design of 6-azasteroidal inhibitors
basedonthe3-keto-4-en-6-aminefunctionalitytomimic thestruc-
Table 19
IC
50
(nM)
Type II 5-reductase,
IC
50
(nM)
102 12 1.4
103 9 <0.10
104 4.5 <0.10
105 30 <0.10
106 150 3.2
107 3.6 <0.10
108 6.9 <0.10
109 20 0.16
110 20 0.12
111 12 <0.10
112 20 0.40
113 1.0 <0.10
114 4.0 <0.10
tural and charge polarization features of the transition state for the
enzyme catalyzed transfer of hydride fromNADPHto testosterone.
The higher reduction potential of ketoenamine compared to that of
,-unsaturated ketone prevents these compounds from acting as
substrates for 5-reductase and they show slow offset inhibition
instead of irreversible as shown by 4-azasteroids [53]. Structure
activity relationship has also been reported by Frye and associates
at C-4, N-6 and C-17 carbamoyl (Fig. 5) [43,84].
Initially a set of N-6, C-1, C-2, C-4 substituted derivatives of 6-
aza-androst-4-en-3-ones (94101) were prepared to explore the
structure activity relationship of A- and B-rings versus type I and
type II 5-reductase (Table 18).
Methylation at N-6 (95) and substitution of C-4 with small
lipophilic groups suchas Cl (96), Br (97) andCH
3
(98) increases type
I 5-reductase activity selectivity 4-fold while type I 5-reductase
activity was decreased by unsaturation (99), 1,2 cycloproponation
(100) and C-2-methylation (101).
By careful optimization of the C-17 substituent along with com-
bining A- and B-ring substitutions, potent dual inhibitors of both
isozymes of 5reductase were obtained (102114) (Table 19) [84].
It was found that optimizing C-17 group resulted in 5-
reductase type I inhibitory activity in 103 with 57-fold increase
of activity in 105. Swapping a methyl ester (106) for an admantyl
ester (108) provides selectivitytowards 5-reductaseI. Preparation
of analogues of 103 resulted in compounds (109112) which were
found to be 16200-fold selectivity towards type I 5-reductase.
Compounds (103, 111, 113 and 114) having ketone at C-17 proved
extremely potent inhibitors of type I 5-reductase. Out of the
group, compound (105) demonstrated efcacy equivalent to Finas-
teride (13) in a castrated rat model of DHT dependent prostate
growth. In general, large lipophilic groups at C-17 provides selec-
tivity against 5-reductase I.
Avariety of C-17 amide-substituted 6-aza-androst-4-en-3-ones
were prepared and evaluated against human type I and type II
steroid 5-reductase in order to optimize potency versus both
isozymes of 5-reductase. Out of the study two series of potent and
selective C-17 amides were discovered, 2,5-disubstituted anilides
and (arylcycloalky1) amides (115121) (Table 20). Evaluation of
some optimal compounds from this series in a chronic castrated
rat model of 5-reductase inhibitor induced prostate involution,
and pharmacokinetic measurements identied compounds (117,
118, 120 and 121) with good in vivo efcacy and half-life in the dog
[85].
B-Homologated analogue of 17-N, N
-diethylcarboxy-6-aza-
androst-4-en-3-one (122) has also been found to be potent
inhibitor of 5-reductase inhibitor with IC
50
=318nM [86].
Bergmann et al. synthesised 7-substituted -4-6-azasteroid
derivatives (123) as 5-reductase inhibitors [87]. But activity data
was not reported for these compounds.
R
1
=H or CH
3
; R
2
=CH
3
; R
3
=hydrogen, Alk-R
4
, X-Alk, C
1-6
-X-
Alk, XCO-Alk, Co-Ar, CO-NH-Ar, CO-NH-Het, etc., where Alk is C
112
straight or branched alkyl, Ar is phenyl, X is O, N or S, Het is
piperidinyl, piperizinyl, pirrolidinyl, pyrrolyl, etc.
6-Azacholesten-3-ones (Table 21) were assayed against both
type I and type II 5-reductase by Haffner [88]. All three com-
pounds were found to be potent dual inhibitors of 5-reductase.
Unlike the 4-azasteroids the cholesterol side chain imparts very
little selectivity between type I and type II 5-reductase. It was
also found that C-7 methyl group might provide a potent 5-
reductase I selective compound. The -C-7 methyl diastereomer
(124) proved to be 7-fold more active 5-reductase I inhibitor
than -diastereomer (125).
Table 20
IC
50
(nM)
IC
50
(nM)
115 4.2 <0.1
116 4.6 <0.1
117 8.8 <0.1
118 1.3 <0.1
119 4.0 <0.1
120 6.8 <0.1
121 0.6 <0.1
FangandSharpin1996synthesizedseveral 6-azaandrostenones
of the general structure (127) as 5-reductase inhibitors [89].
16-Aryloxy, -alkoxy and heteroaryloxy 6-azasteroids of the
general formula as given belowwere synthesised by Aster et al. and
the compounds were found to be potent inhibitors of 5-reductase
[90]. Compound (128) was found to be potent inhibitor of human
5-reductase type I with IC
50
in the range of 0.11000nM.
Rahier and Taton have reported synthesis of several novel 6-
aza-B-homosteroids but they were not tested for 5-reductase
inhibitory activity [91]. Later in 2000 and 2001, Wenge et al.
[92] and Xie et al. described the synthesis of 6-azasteroids as
Table 21
Compounds Type I 5-reductase k
i
(nM) Type II 5-reductase k
i
(nM)
124 0.8 7.9
125 1 1.2
126 1 2.3
potent phosphatidylinositol phosphalipase C (PI-PLC) inhibitors
[93]. Kasal et al. in 2005 reported an efcient synthesis of 6-
aza-allopregnanolone as neurosteroid analogues but not evaluated
them for 5-reductase inhibitory activity [94].
7. 7-Azasteroids
Some 7-azasteroids were synthesized in early 1970s
[95]. Morzycki and Sicinski reported the synthesis of 6,7-
diazacholestane derivatives but they were not evaluated for
the 5-reductase inhibitory activity [96].
8. 8-Azasteroids
Several 8-azasteroids have been synthesized [97] and discussed
as antifungal agents [98,99] but none has been reported as 5-
reductase inhibitor.
9. 9-Azasteroids
No work has been published on 9-aza steroids as 5-reductase
inhibitor although some fungicides have been known from this
category [100].
10. 19-Nor-10-azasteroids
On the basis of the molecular model of active site for type II
isozyme and to increase the activity and selectivity of compounds
towards both 5-reductase type I and 5-reductase type II.
Guarna et al. synthesized a novel class of compounds 19-nor-10-
azasteroids (Tables 22 and 23) [101].
Best results were obtained with 9:1 mixture of
9(11)
(133)
and
8(9)
(134) 17 -(N-tert-butyl carbamoyl)-19-nor-10-aza-
4-androsten-3-one as it was found to be a good inhibitor of
5-reductase type I and 5-reductase type II. The enamine struc-
ture of ring A of 10-aza-steroid (136) is analogous to that of the
substrate like transition state. The presence of N atom at position
10 increases the nucleophilic character of the carbonyl group and
stabilizes the carbocation intermediate (137) by delocalization at
the positive charge.
Table 22
In vitro screening of compounds 129135 against human steroid 5-reductase type
II.
Compounds IC
50
(nM) Finasteride
IC
50
(nM)
IC
50rel
(nM)
(IC
50
rel =IC
50
compound/IC
50
Finasteride)
129 4600 2990 3.4 2.2 1389 1295
129:130=5:1 4600 960 4.1 0.7 1123 318
131:132=22:1 2900 1190 3 1.4 981 609
133:134=9:1 37 6.7 2.2 0.4 16.9 0.4
133:134=3.5:1 150 33 4.3 1.5 34 12
135 460 229 5.5 2.1 83 52
Table 23
In vitro screening of compounds 129135 against human steroid 5-reductase type
I in DU-145 cells.
Compounds IC
50
(nM) IC
50rel
(nM) Selectivity 5-reductase II:
5-reductase I
129:130=5:1 263 63 6.7 2 1:17
131:132=9:1 127 12 2.8 0.4 1:1
135 1134 288 24.4 7 2.5:1
The inhibitory potency of these compounds depends on the
presence of bridgehead N-10 atom conjugated with 4-en-3-one
moiety in A-ring, unsaturation in C-ring and substituent at C-
17 position. 19-nor-10-aza steroids have low transitional barrier
energy values and more exible as compared to 6-aza or 4-
azasteroids [102].
Some 10a-azasteroids were also synthesized from fusidic acid
but were not evaluated for 5-reductase inhibitors [103]. Guarna
et al. also synthesized 17-[N-(phenyl) methyl/phenyl-amido]
substituted 10-azasteroids. Unexpectedly, 5-H compounds were
found more active than their 5-H counterparts, with (138)
(IC
50
=279 and 2000nM toward isoenzymes I and II, respectively)
and (139) (IC
50
=913 and 247nM toward isoenzymes I and II,
respectively) being the most potent compounds of the series
[104].
11. 11-, 12a-, 13-Azasteroids
Though many 11-azasteroids [105107], 12a-azasteroids [108]
and 13-azasteroids [109] have been prepared but 5-reductase
inhibitory activities have not been reported.
12. 15- and 16-Azasteroids
Many 15-azasterols have been synthesized as antifungal agents
[110112] but none of themhave been evaluated for 5-reductase
inhibitory activity. 16-Azasteroids have been synthesized but none
of the compound has evolved as 5-reductase inhibitor [113,114].
13. 17- and 17a-Aza-D-homosteroids
Regan and Hayes, in their exemplary work, have synthe-
sized several 17- and 17a-aza-D-homosteroids from several
17-ketosteroid oximes [115]. But 17a-azasteroids attracted more
attention when chandonium diiodide was established as a potent
neuromuscular blocker [116]. 17 and 17a-Azasteroids have been
found to possess numerous biological activities like gamma amino
butyric acid (GABA) receptor antagonistic [117119], antifungal
[120], antineoplastic, mutagenic [121,122] and anti-inammatory
activity [123]. The most interesting aspect concerning 17-D-homo-
azasteroids is the possibility of inverted action or backbinding
as proposed by MacDonald et al. [124]. Their proposition was based
on the fact that the steroids have the potential to bind in two
orientations in the active site of various metabolizing enzymes.
Marcus andTalalay[125] rst reportedthat 3(17) -hydroxysteroid
dehydrogenase converts both T (1) and dehydroepiandrosterone
(141) to androst-4-ene-3,17-dione (140) (Fig. 6a). Other examples
of enzyme inhibition by inverted steroids have also appeared. The
oxiranes 143 and 144 were found to be active site-directed, irre-
versible inhibitors of 3-oxo-
5
-steroid isomerase (Fig. 6b) [126]
and the bromoacetates 147 and 148 act as afnity labels for estra-
diol 17-dehydrogenase (Fig. 6c) [127]. Research on 5-reductase
Table 24
In vitro screening of compounds 149152 against
human steroid 5-reductase.
Compounds IC
50
(M)
149 4
150 15
151 12
152 40
inhibitors has shown that steroids without side chains can bind to
enzymes with the A-ring of the substance simulating the D-ring of
the substrate, while the D-ring emulates the A-ring. This could lead
to 17-D-homo-azasteroids exhibiting same mechanismof action as
4-azasteroids. However, uptonow, researchhas beenconcentrated
on 4-azasteroids as 5-reductase inhibitors and 17a-azasteroids
remainedunexploredavenueas far as their 5-reductaseinhibitory
activity is concerned. Some 17a-azasteroids (149152) evaluated
for 5-reductase inhibitory activity are summarizedinthe Table 24
[124].
14. Diazasteroids
Eberbach and coworkers reported in 1996 a novel access to
4,13-diazasteroid derivatives but they were not evaluated for 5-
reductase activity [128]. In the same year Stuart et al. rst reported
4,17-diazasteroids as potential inhibitors of 5-reductase. The
Finasteride 17-aza-isomer (153) proved to be potent inhibitor
of 5-reductase II although less active than Finasteride (13) and
its congeners. 4-Methylation (154) lowered the inhibition of the
5-reductase II enzyme. Removal of
1(2)
unsaturation led to the
formation of compound (155) that is dual inhibitor of 5-reductase
type I and type II and 4-methylation of 155 led to the increase in
activity in 156. While compound with
5(6)
(157) showed only a
moderate inhibition of 5-reductase II activity (Table 25) [129].
Fig. 6. (a) Action of 3(17) -hydroxysteroid dehydrogenase, (b) action of 3-oxo-
5
-
steroid isomerase, and (c) action of estradiol 17-dehydrogenase.
8,13-Diaza steroids were also synthesized by Gnds et al. in
1998 but not evaluated for 5-reductase inhibitory activity [130].
15. 11,13,15-Triazasteroids
Hirota et al. reported in 1995 the synthesis of 11,13,15-
triazasteroid derivatives to investigate antidepressive activity.
These analogues were also evaluated for anti-platelet aggrega-
tion activity and some derivatives exhibited positive action but no
5-reductase activity has been investigated in these categories of
steroids [131].
16. B,D-Dihomo-azasteroids
Several steroidal B,D-dihomolactamhave been synthesized and
evaluated for antitumour activity but no 5-reductase activity has
been reported from this group till date [132,133].
17. Des-AB-azasteroids
Trehan et al. synthesized des-AB-azasteroids but 5-reductase
activity studies were not done [134].
Steroidal 5-reductase inhibitors which are extranuclear, i.e. in
which nitrogen is not the part of steroidal nucleus but forms part
of the side chain or attached group have also been explored as 5-
reductase inhibitors, therefore are discussed next.
Table 25
IC
50
(nM)
IC
50
(nM)
153 765(70) 10.3(1.1)
154 477(29) 174(42)
155 2200(140) 40.1(2.8)
156 28.0(2.1) 3.6(0.3)
157 7000 52.0(7.8)
4-MA
a
(12) 6.4(0.2) 0.4(0.04)
a
N,N-Diethyl-3-oxo-4-methyl-4-aza-5-androstrane-17-carboxamide (4-MA)
was used as a standard reference.
Table 26
In vitro screening of compounds 158166
against human steroid 5-reductase.
Compounds K
i,app
(nM)
158 30
159 718
160 26
161 712
162 7
163 3036
164 32
165 35
166 50
18. Steroidal 3-carboxylic/phosphonic/phosphinic acids
A number of 3-androstene-3-carboxylic acids (158166)
(Table 26) were designed to mimic the putative enzyme-bound
enolate intermediate by incorporating sp
2
-hybridized centers at
C-3 and C-4 and, most critically, an anionic carboxylic acid at
C-3 as a charged replacement for the enolate oxyanion. Because
of presumably favorable electrostatic interaction between the
carboxylate and the positively charged oxidized cofactor, the
acrylate preferentially binds in a ternary complex with enzyme
and NADP
+
, which leads to the uncompetitive kinetic mechanism
[135137]. Activity is enhanced in analogues possessing an addi-
tional unsaturation at C-5 (162167) along with
3
-unsaturation.
At C-17, diisopropyl (158) and pivalyl (163) amides were optimal.
Epristeride (SK&F 105657) (163) entered the clinical trials for
treatment of BPH and is a potent inhibitor of 5-reductase II while
a weak inhibitor of 5-reductase I.
Aseries of estratriene-3-carboxylic acids containinganaromatic
A-ring had also been synthesized (167171) (Table 27) with struc-
tural variations in the C-2 and C-4 substituents, in the degrees of
Table 27
against human steroid 5-reductase.
Compounds K
i,app
(nM)
167 20
168 30
169 10
170 35
171 36
unsaturation in the B- and D-rings, and in the C-17 carboxamide
alkyl groups. Despite lacking C-19 methyl group these compounds
were found to be potent inhibitors of 5-reductase [138].
Nitro derivatives also showed interesting structure activity
relationship patterns compared to carboxylic acids, compound
(172) was found to be potent competitive inhibitor by binding to
E-NADPHcomplex [139]. The sulphonic acid (173) [140], phospho-
nic acid (174) and phosphinic acid (175) also proved to be the
potent inhibitors of human 5-reductase but not so of rat 5-
reductase [141]. The afnities of phosphonic acid are relatively
less than phosphinic acid derivatives because the increased bulk
at the 3-substituent, leading to a steric intolerance for binding to
enzyme. Overall 3-phosphosteroids were weaker inhibitors than
their corresponding steroidal-3-carboxy steroids. The function of
the C-3-moiety is presumably to act as an H-bond acceptor from a
residue in the enzyme, which would normally donate a hydrogen
bond to stabilize the enolate. Since the negatively charged groups
(CO
2
) or isosteres of the carboxylate (NO

2
) best mimic this
interaction it indicates that a pK
a
-matched H-bond with a Lys or
Arg donor may be operative. In addition, an interaction between
the negatively charged C-3-moiety and the positively charged
NADP
+
cofactor after the enzyme has turned over substrate is
possible, especially if the cofactor lies directly under the A-ring of
the steroidal skeleton in the transition state and mimics thereof.
Compound 176 was not as active due to the presence of alcoholic
group as it was not able to provide sufcient negative charge and
hence was a weak inhibitor of rat and human 5-reductase.
19. Diazoketone steroids
The primaryevidence of a dramatic increase inthe afnityof 5-
reductase and an inhibitor with a 5-juncture of A-/B-ring and sp
2
hybridization at the C-3 and C-4 positions was obtained from the
inhibition with a mechanism-based inhibitor (5,20R)-4-diazo-21-
hydroxy-20-methyl-pregn-6-en-3-one (177) (RMI-18,341). Dia-
zoketone (177) had been reported to be a potent time-dependent
inhibitor witha K
i
of 35nM(time-dependency is consideredindica-
tive of irreversibility) [142].
A mechanism of inhibition was proposed that the protonation
steps implicated in the normal enzymatic transformation activates
the diazoketone functionality to a diazoniumion that could further
alkylate some nucleophilic residue at the active site [143].
20. 4-Substituted steroids
The observation that an excellent inhibitor possessed a con-
jugated system (sp
2
sp
2
sp
2
) at C-3, C-4, and C-5 positions
of A-ring of steroids together with a lipophilic group at C-17,
a range of 4-substituted-3-oxo-4-androstene-17(-carboxamides
(180183) (Table 28) were prepared and compared with the
Table 28
In vitro screening of compounds 180183 against human 5-reductase.
Compounds Human 5-reductase
type I (transfected 293
cells) (IC
50
nM)
Human 5 reductase
type II (transfected
SW-13 cells) (IC
50
nM)
180 2.9
181 709 437
182 >1000 192
183 981 387
Finasteride (13). Out of these 4-cyano compounds were found
to be potent inhibitors of 5-reductase type II enzyme and
substitution with groups like thiol led to decreased activity.
This series of compounds were also found to be potent andro-
gen antagonists [144]. Fei et al. carried out the synthesis of
some novel 4-triuoromethylsteroids and proposed them as novel
5-reductase inhibitors. Out of the series 4-triuoromethyl-N-(t-
butyl)-4-androsten-17-carboxamide (184) emerged as the most
potent inhibitor being 4 times more active than Finasteride (13)
[145]. 4-Cyanoprogesterone (185) was also found to be a potent
inhibitor of both rat and human 5-reductase enzymes (IC
50
val-
ues =0.045and0.050M, respectively). Themechanismof actionof
4-cyano steroidal inhibitor was assumed to be the transition state
inhibitor because on reduction by the enzyme compound would
form a stable 53-enol that would remain tightly bound to the
active site [146,147].
21. Steroidal oximes
A number of pregnenolone (186190) and progesterone
(191194)-based steroids were synthesized bearing a oxime group
connected directly or via a spacer to the steroidal D-ring, capable to
form a coordinate bond with haeme iron of enzyme 5-reductase.
In contrast to the pregnenolone derivatives which showed no inhi-
bition of 5-reductase isozyme I and II, progesterone derivatives
possessed marked inhibition towards type II.
Inhibitory potency of synthesized compounds against target
enzyme using whole cell assay revealed that C-20 oxime (191) dis-
played strong inhibition against both isozymes (IC
50
=1.63 against
human type I and 0.58M against human type II). Unsaturation
in ring D (192 and 193) in conjugation with oxime group further
enhances inhibitory activity. Almost complete loss of activity has
been found toward type I in the derivative with keto group at C-6
(194).
Transferring the oxime group from positions 20 to 21
caused an increased selectivity toward type II isozyme. Z-21-
Hydroxyiminopregn-4-en-3-one (195) was found to be a potential
inhibitor of the type II (IC
50
=1.95M against human type I and
0.30M against human type II).
However, none of the compounds showed activity near to that
of the reference drug Finasteride (13) (IC
50
values being 45 and
3nMfor type I and type II, respectively, inthe corresponding study)
[148].
22. Steroidal tetrahydrooxazin-2-ones
Wlng et al. synthesized a novel series of steroidal
tetrahydrooxazin-2-ones (196201) containing heterocycles
involving O and N heteroatoms at position 17 of androst-4-en-
3-one, respectively, as 5-reductase inhibitors. The IC
50
values of
compounds vary between 270 and 600nM. The relative inhibitory
effect of the unsubsituted N-phenyl compound 196 is 0.20. Con-
cerning the effects of substituents at position 4 of the phenyl
ring in 196, the introduction of an ethyl (197) or ethoxy (199)
group resulted in a weak enhancement of 5-reductase inhibition.
Substitution with halogens (200 and 201) or methoxy (198) caused
lowering of inhibition ability [149].
Steroid5-reductase inhibitors that donot containany nitrogen
either as part of ring or extranuclear but yet found to inhibit 5-
reductase are discussed next.
23. 16-Substituted steroids
A series of 16-methyl substituted derivatives of androst-4-
ene and estr-4-ene originally prepared as antiandrogens, were
tested for their inhibitory activity on rat and human prostatic
5-reductase. The inhibitory activity data indicated that IC
50
increases in sequence in derivatives bearing 16-methyl (203),
16-methyl (204) and 16,16-dimethyl substituents (205). Acy-
lation of 17-hydroxy group signicantly increases the inhibitory
potency (IC
50
(207) =4.8nM, IC
50
(206) =23.5nM in rat prostate
and IC
50
(207) =0.52nM, IC
50
(206) =0.62nM in human prostate).
Overall, in human prostate homogenates IC
50
varies between 0.6
and 120m while in rat prostate it ranges from 1.6 to 1000M.
This shows enzyme of human prostate is more sensitive than
that of rat prostate to methyl substituted compounds. Overall
16-methyl steroids were found to be weak inhibitors both in rat
and human enzymes compared to the existing ones [150].
Certain 19-nor analogues have also been synthesized in order to
improvetheinhibitoryactivityin16-methylatedderivatives. TSAA-
291(16-ethyl-17-hydroxy-4-estren-3-one) (208) was foundtobe
the rst anti-androgen known to have dual action of competitive
inhibition of 5-reductase activity and androgen receptor complex
formation. It showed a K
i
of 1400nMto the puried nuclei fromrat
prostatic tissues [151].
24. 6-Methylene steroidal derivatives
2
,3
-Tetrahydrofuran-2
-spiro-17-(6-methylene-4-
androsten-3-one) (209; L612,710) is a potent time-dependent
inhibitor which causes the highest percentage of inhibition (81%)
of rat prostatic 5-reductase enzyme. The structure activity
relationship showed that 3-oxo-4-ene functionally was essential
to the inhibitory activity and that substituents at C-17 inuenced
the inhibitory potency. The presence of the C-19 methyl group was
not essential to the activity. The A-ring appeared to interact with
the entire active site of the enzyme. Furthermore, the afnity of an
inhibitor to the enzyme was greatly enhanced by the introduction
of a methylene group at C-6 whereas activity was completely lost
with a large radical such as iodomethylene group at C-7. Thus a
series of 6-methylene steroids were prepared and examined as
irreversible inhibitors of rat prostatic 5-reductase [152]. Another
6-methylene steroid that is potent inhibitor due to priming
of its dienone group by electrophilic activation toward nucle-
ophilic attack at the 6-methylene group is having structure (210)
[153].
25. Seco steroids
(4R)-5,10-Seco-estra-4,5-diene-3,10,17-trione (211) and (4R)-
5,10-seco-19-nor-pregna-4,5-diene-3,10,20-trione (212) were
rst found to be non-competitive and possibly irreversible
inhibitors of epididymal 5-reductase. Radiographic crystallog-
raphy studies of both compounds showed that the conjugated
allenic 3-oxo-5,10-secosteriod (211) has a conformation similar to
that of the normal tetracyclic steroid dione. Both compounds were
non-competitive inhibitors of 5-reductase and have an afnity
label for the enzyme with K
i
of 5470 and 980nM, respectively
[154,155].
26. Derivatives of natural substrate: pregnane
As a consequence of the important observation that pro-
gesterone and deoxycortisone inhibits the synthesis of dihy-
drotestosterone by competing with 4-en-3-one function of the
testosterone for the 5-reductase enzyme it led Voigt and cowork-
ers to synthesize number of progesterone derivatives [37,38]. The
satisfactory result of 4-cyano-progesterone (185) [146], which
possessed marked inhibitory activity for 5-reductase enzyme,
stimulated great deal of interest to synthesize various 4- and
6-halo-progesterone analogs (213217). These compounds were
found to be potent antiandrogenic in nature when tested against
gonadectomized hamster seminal vesicles and were also found to
be inhibitors of 5-reductase [156158].
Bratoeff et al. evaluated the antiandrogenic and 5-reductase
inhibitory activity of various 16-phenyl substituted-D-homo
compounds (218219), 16-methyl substituted steroids (220222),
4-bromo compound (223) without a methyl group at C-16 and the
epoxy compounds (224225). Compounds 219, 222 and 223 were
found to possess both antiandrogenic and 5-reductase inhibitory
activity better than the Finasteride (13) [158,159]. The trienones
having a more coplanar structure reacts faster with the nucle-
ophilic portion of the enzyme in a Michael type addition reaction
to forman irreversible adduct with a concomitant inhibition of the
enzyme 5-reductase than the dienones.
A range of 4-bromo-17-substituted-4-pregnene-3,20 diones
were also synthesized and evaluated as 5-reductase inhibitors
on gonadectomized hamster seminal vesicle and ank organs.
Small diameter of the pigmented ank organ and great reduction
in the weight of seminal vesicle has been found with the com-
pounds having p-uorobenzoyloxy (226) and p-chlorobenzoyloxy
(227) indicating that the presence of more electronegative sub-
stituent at C-17 position (p-halosubstituted phenyl) and halogen at
C-4 enhances the antiandrogenic activity as well as 5-reductase
inhibitory activity [160,161].
Several new pregnane derivatives were also synthesized and
evaluated by the conversion of [
3
H] T to [
3
H] DHT in Penicillium
crustosum broths and the conversion of [1,2-
14
C] sodium acetate
into lipids. Compounds 228 and 229 were found out to be potent
5-reductase inhibitors as they inhibit conversion of T to DHT and
also decreased the incorporation of radiolabeled sodium acetate
into lipids of the ank organs [162].
Cabeza et al. also reported the 5-reductase inhibitory activ-
ity and the antiandrogenic effect of novel 16-bromo substituted
trienedione, 16 methyl substituted dienedione and the triene-
dione (230232). Compounds 230 and 231 were found to Exhibit
5-reductase inhibitory activity higher than the commercially
available Finasteride (13) [163].
The in vitro inhibitory activity of some novel progesterone
derivatives was also determined and they were evaluated as
5-reductase inhibitors as well as antagonists for the androgen
receptor. The appropriate homologues extended by a methylene
group at C-6 (233236) showed better activity due to the pres-
ence of exocyclic double bondthat canreact faster withthe enzyme
in a Michael type addition reaction than the corresponding endo-
cyclic diene. Compounds 233 and 234 showed IC
50
values of 19 and
100nM, respectively [164,165].
In compound 237 which is an epoxy compound the nucleophilic
enzyme attacked the electrophilic center at C-6 and in this process
inhibits the enzyme. Several 3-substituted 4-pregnene-6,20-dione
derivatives (238246) have been synthesized and were evaluated
for antiandrogenic as well as 5-reductase inhibitory activity. The
synthesized steroids have an ,-unsaturated carbonyl moiety
in common. It was found that accessible electrophilic -carbon
of an ,-unsaturated carbonyl moiety reacted very readily with
a variety of nucleophiles to form Michael adducts. The rst step
involved the formation of an enzyme-steroid activated complex
and in a subsequent step the nucleophilic portion of the enzyme
(amino group) attacked the conjugated double bond of the steroid
in a Michael type addition reaction to form an irreversible adducts
[166].
The IC
50
values of the compounds were found to increase pro-
gressively as the substituent on the phenyl group of the ester
side chain at C-3 became more electropositive, i.e. compound
241 has an IC
50
value of 3.0nM as compared to compound
243 which has an IC
50
value of 4.0nM. On the other hand the
compounds (244246) having saturated 4-pregnene-6,20-dione
skeleton for, e.g. 245 exhibited higher IC
50
value (3.7nM) as com-
pared to the unsaturated ones (240243) for, e.g. 241 with a
value of 3.0nM. It was also found that the presence of halo-
gen substituents in ester moiety at C-3 as well as double bond
at C-16 increased the binding afnity for the androgen receptor
[167].
Several new progesterone derivatives were also synthesized by
the same group having dienone moiety as reported earlier. Some of
them (247248) were found to have high 5-reductase inhibitory
activity like 248 showing an IC
50
value of 0.5nM as compared to
Finasteride (13) showing an IC
50
value of 8.5nM in the same study
[168,169].
Bratoeff et al. synthesized two novel steroidal carbamates
(249250) which are the esters of carbamic acid with substituents
at the amino and esters ends (NHRCOOR
1
) and proposed them
as novel class of inhibitors for human and hamster steroid 5-
reductase. These compounds have a longer half-life and are
hydrolyzedslowly inthe liver due to whichthey have a better phar-
macological activity when compared to the conventional esters.
Compound 249 has got a similar IC
50
value (10nM) as that of Finas-
teride (8.5nM) (13) while compound 250 has a higher IC
50
value of
about 50nMapparently due to the presence of large bromine atom
[170].
Working on similar lines some more novel 4,16-pregnadiene-
6,20-dione derivatives were synthesized and evaluated as 5-
reductase inhibitors. In this work, it has been demonstrated that
compounds containing chlorine (251), bromine (252), iodine (253)
atoms, and(254); without any substituent inthe ester moiety) at C-
3 produce a signicant decrease of the prostate weight in castrated
animals treated with testosterone (1). Therefore, it was proposed
that the ester moiety at C-3 is functioning as a pharmacophore,
Table 29
IC
50
(nM)
IC
50
(nM)
262 6500
263 460
264 30
265 60
enriched by the presence of halogens in these steroidal derivatives
leading to the increase in the inhibition of 5-reductase enzyme
as determined by the IC
50
values. Compound 252 was found to be
most potent with an IC
50
value of 1.8nM while compounds 251
and 253 showed values 14 and 10nM, respectively, in comparison
to Finasteride (13) having value 8.5nM. Compound 254 was not
that active when compared to halogenated compounds thus
further demonstrating the need of a halogen atom in the ester side
chain [171].
Recently, Cabeza et al. synthesized several C-6 substituted and
unsubstituted pregnane derivatives as potential 5-reductase
inhibitors. It has been found that steroids that lack a chlorine
atomin C-6 (255257) exhibited a higher capacity for inhibition of
the activity of 5-reductase (IC
50
in the range of 2563nM) than
the compounds (258260) having this atom (IC
50
in the range
of 920990nM in comparison to Finasteride (13) having an IC
50
8.5nM). The presence of bromine atom in C-6 of compound 261
however doesnt affect the inhibitory activity of enzyme (IC
50
being 33nM). Also, the presence of an ester moiety in C-17
on the steroidal skeleton tends to increase the inhibition of the
activity of the enzyme [172].
27. Non-steroidal 5-reductase inhibitors
A number of classes of non-steroidal inhibitors of 5-reductase
have now been identied. It was anticipated that the use of non-
steroidal templatecandecreasethepotential interactionwithother
enzyme or receptor of the steroidal endocrine systemand can limit
the complexity of target compound synthesis [173]. They have in
fact emerged either from the design of compounds mimic of azas-
teroidal inhibitors, generally by the formal removing of one or more
rings fromthe azasteroidal structure or by early non-steroidal lead
(ONO-3805) (261) which was prepared as leukotriene synthesis
inhibitor [174] or by high throughput screening. These com-
pounds are generally thought to act all as competitive inhibitors
vs. testosterone with exception of the epristeride analogues which
are uncompetitive inhibitors. Non-steroidal inhibitors include
benzo[f]quinolinones, pyridones and quinolinones which were
mimics of 4-azasteroid inhibitors. Benzo[c]quinolinones were syn-
thesized as mimics of 6-azasteroids while benzo[c]quinolizinones
were designed as mimics of 10-azasteroids. The most potent and
selective inhibitors of human type I 5-reductase are found among
these classes of compounds. Almost all the other non-steroidal
inhibitors can be grouped as carboxylic acid (generally butanoic
acid) derivatives which are thought to act as non-competitive
inhibitors versus testosterone in analogy to ONO 3805 (261).
28. Mimics of 4-azasteroids: benzo[f]quinolinones
Benzo[f]quinolinones were the rst non-steroidal inhibitors
prepared by the Lillys researchers. They were derived by the
removal of the D-ring from 4-azasteroids and replacing the C-ring
with an aromatic one [175]. Most of these compounds are type I
selective, although dual inhibitors can be obtained if an appropri-
ate substitution is present at the position 8 on the aromatic ring.
Two main classes of benzo[f]quinolinones have been described,
the hexahydro derivatives (262265), which have an unsaturation
at positions 4a10a, and the octahydro derivatives (266271). In
general octahydro derivatives are more potent inhibitors than the
corresponding 4a10a unsaturated compounds (Tables 29 and 30)
andinbothseries the potencytowardtype I 5-reductase increases
if an halogen atom is present at position 8 (in particular a Cl atom)
and a methyl group at position 4; in fact the most potent inhibitor
of the series is LY191704 (268) with IC
50
=8nM (Table 30). This
molecule has progressed into human clinical trials.
The quantitative structure activity relationship study of these
compounds has focused on the effect of 8 substituent on the aro-
matic ring, which can be accounted for by its lipophilic character
[176]. They foundthat the optimumactivity may reside inthe prop-
erty space around the chlorine substituent. The substitution of the
8-Cl atomby a F (270) or a Br atom(271) decreasedvery slightly the
potency. Finally, several kinds of substituents, including complex
aromatic groups, were introduced at the position 8 [177], and some
potent type I selective inhibitors suchas compounds 272274 were
prepared.
29. Pyridones, quinolinones and piperidines
Abell et al. synthesized a number of tricyclic thiolactams
(275276), aryl acid (277), bicyclic lactams (278281) and bicyclic
thiolactam (282) and evaluated them in vitro as inhibitors of type
I and type II steroid 5-reductase (Table 31). Removal of two
or more rings from 4-azasteroids resulted in a strong decrease
of potency. The tricyclic thiolactams were found to be selective
type I 5-reductase inhibitors and in general were less active
than the corresponding lactams. The aryl acid 277 showed good
dual isozyme inhibitory properties with signicantly enhanced
type II activity. Bicyclic lactams, in general, were found to be less
active against type I 5-reductase than the tricycles. For example,
compounds (278279), lacking the B and D steroidal rings, were
poor type I 5-reductase inhibitors, with the highest potency
associated to the presence of the Cl atom on the aromatic ring of
279 [178]. A styryl (or azo) substituent dramatically enhances type
II activity (and indeed type I activity with the bicycles) (280281)
and provided dual inhibitors of type I and type II.
Table 30
IC
50
(nM)
IC
50
(nM)
266 60
267 17
268 8 10,000
269 11
270 35
271 35
272 59 >10
273 6 1,400
274 6 1,340
Hartmann and coworkers synthesized pyridones of the general
formula 283 and 284 where the B- and C-rings of the steroid sys-
tem have been replaced by an acyclic linker but these compounds
display relatively weak activity versus both the rat and human 5-
reductase isozymes (K
i
>20M) [179181].
Their poor potency however illustrates the need for both A- and
B-rings tobe present withthe correct fusionpatternfor goodrecog-
nition at the enzyme active site. A series of 5-phenyl substituted
1-methyl-2-pyridones have also been prepared and tested against
human and rat 5-reductase type I and type II. Compound 285
bearing bulky carboxamide substituents exhibited excellent 5-
reductase type II inhibitory activity with IC
50
value of 10M[182].
McCarthy and coworkers have recently synthesized a series of
4
-substituted 5-aryl pyridones along with corresponding 1-aryl-

pyridone derivatives and tested them against 5-reductase type
I and type II expressed in transfected human embryonic kidney
cells to examine structure activity relationship for the 4
position
in pyridones.
Weak inhibition was observed against the type I isozyme for
4
-N-substituted acetamide compounds (286289) while potent

inhibitionof type I isozyme was observedfor compound290having
4
-benzoyl substituent and also for compounds (291292) having

long carbon chain tethers attached to the 4
-acetamide (Table 32).

Thus further proving that large hydrophobic groups are tolerated
in a region of the active site not involved in the enzymatic reaction
[183].
Fewquinolinone derivatives suchas 6-substituted1H-quinolin-
2-ones (293294) and 2-methoxy quinolines (295296) have also
been synthesized. The most active inhibitor for the human type
II isozyme was 6-[4-(N,N-diisopropylcarbamoyl) phenyl]-1H-
quinolin-2-one 293 having K
i
80085nM, showing mostly
competitive inhibitory patterns. A type I selective inhibitor could
be identied with 6-[4-(N,N-diisopropylcarbamoyl) phenyl]-
N-methyl-quinolin-2-one 294 (IC
50
=510nM) but 2-methoxy
quinolines were not found to be active [184].
Hartmann and coworkers synthesized and evaluated a series of
2
-substituted 4-(4
-carboxy- or 4
-carboxymethylbenzylidene)-
N-acylpiperidines as active steroid 5-reductase type II inhibitors.
They synthesized several compounds from N-acyl-4-benzylidene-
piperidine-4
-carboxylic acids. In the dicyclohexylacetyl series,

uorination in the 2-position of the benzene nucleus (297),
exchange of the carboxy group by a carboxymethyl moiety (298)
and combination of both structural modications (299) led to
highly active inhibitors of the human 5-reductase type II isozyme
with IC
50
values of 297, 298 and 299 being 11, 6 and 7nM, respec-
tively, incomparisonto Finasteride (13) having value of 5nM[185].
Earlier Hartmann et al. have reported a series of N-substituted
piperidine-4-(benzylidine-4-carboxylic acids) (300303) as potent
non-steroidal dual inhibitors of 5-reductase.
Table 31
IC
50
(nM)
IC
50
(nM) or
percentage inhibition
275 377 13.2% @ 40M
276 183 21.6% @ 40M
277 152 340
278 2477 13.5% @ 40M
279 1690 12,350
280 302 579
281 107 617
282 3360 14% @ 40M
Table 32
Compounds Type I 5-reductase
(% inhibition at 10M)
Type II 5-reductase
(% inhibition at 10M)
286 8
287 6
288 6
289 3
290 61
291 43
292 33
Finasteride (13) 453 (IC50
(nM)) 25 (IC
50
(nM))
In rat, compounds 300 (IC
50
=3.44 and 0.37M for type I and
type II, respectively) and 302 (IC
50
=0.54 and 0.69M for type I
and type II, respectively) displayed the best inhibition toward both
isozymes. Compound 301 showed a strong inhibition toward type
II human and rat enzyme (IC
50
=60 and 80nM) but only a moderate
activity versus type I enzyme (IC
50
approximately 10Mfor rat and
human enzyme). Compound 303 (IC
50
in human type II enzyme
being 0.26Mand in rat type II enzyme being 0.29M) was found
to be a moderate dual inhibitor probably due to higher exibility
of the open ring substituent [186].
Methyl esters of N-(dicyclohexyl)acetyl-piperidine-4-
(benzylidene-4-carboxylic acid) (304) were designed and
monitored for dual inhibition toward type II isozyme in BPH
cell free preparation and for type I isozyme in DU 145 cells.
Methyl esters, applied as hydrolytically stable precursor drugs to
facilitate cell permeation, will yield the corresponding carboxylic
acids as type II inhibitors after hydrolysis in the target organ. The
esters themselves stable in human plasma and Caco-2 cells act
as potent drug toward 5-reductase type I. Thus, dual inhibition
of 5-reductase type I and type II can be achieved by applying a
single parent compound [187].
30. Mimics of 6-azasteroids: benzo[c] quinolinones
On the basis of 6-aza-androst-4-en-3-one derivatives (Fig. 5) in
which a vinylogous amide was inserted into a steroid nucleus as a
transition state mimic for conversion of T (1) to DHT (2) and Lillys
Table 33
against recombinant 5-reductase I expressed
in CHO cells.
Compounds IC
50
(nM)
308 5130 130
309 176 17
310 459 118
311 137 58
312 49 19
313 20 8
314 7.6 0.9
315 14.3 5.9
316 8.5 2.1
317 204 49
Benzoquinoline derivatives (267268), novel phenanthridin-3-one
derivatives (305307) were synthesized having vinylogous amide
pharmacophore.
Although compounds were found to be 5-reductase type I
selective and poor inhibitors of 5-reductase type II but overall
these compounds did not showed promising inhibitory activity.
The potency of compounds was found to increased from 305
(K
i
10M) to 306 (K
i
=1.1M) and 307 (K
i
=0.92M) this was
due to the presence of methyl group on the A-ring corresponding
to the 4-Me of Eli Lilly inhibitors. This effect is due to the presence
of hydrophobic pocket in the active site of enzyme which is able to
accommodate a small alkyl group located at the position 4 of the
A-ring of these tricyclic inhibitors [188].
31. Mimics of 10-azasteroids: benzo[c] quinolizinones
Guarna et al. had synthesized two series of benzo[c]quinolizin-
3-ones as novel inhibitors of human5-reductasetypeI: 4aH-series
with a double bond between the positions 1 and 2 (308311) and
1H-series with a double bond between the positions 4 and 4a
(312317). The efcacy and selectivity of these compounds
have been demonstrated on recombinant human 5-reductase
type I expressed in CHO cells but they displayed very poor or
no inhibition towards 5-reductase type II (Table 33). Increased
activity of the compounds of 1H-series than those of corresponding
inhibitors of 4aH-series has been attributed to the presence of
double bond enabling conjugation between carbonyl and nitrogen
atom [189191].
Fig. 7. SAR for
4
-benzo[c] quinolizin-3-ones.
The presence of a methyl group at position 4 (311, 313, 314,
and 316) associated with a substituent at position 8, gave potent
compounds in comparison with Finasteride (13) and the known
5-reductase I selective inhibitor LY191704 (268). All compounds
inhibitedthe enzyme througha reversible competitive mechanism.
The structure activity relationship carried out on this class espe-
cially methyl group at positions 1, 4, 5, 6 and 8 can be summarized
as follows (Fig. 7) [191].
It was found that presence of substituent at position 8, either
a chlorine or methyl group, generally increased the potency of
the inhibitors. Thus compound 309 and 310 were potent were
more active than unsubstituted compound 308 in 4aH-series. Sim-
ilarly in 1H-series compounds 312 and 314 were more potent than
unsubstituted compounds due to presence of 8-chlorine group. The
introduction of a methyl group at position 4 was found to increase
the potency in both series with effect being higher in 1H-series. A
very strong increase of potency is observed in 8-chloro-4-methyl
derivative 314 when compared to 4-methyl unsubstituted com-
pound 312. The substitution with a methyl group at position 6 also
affects potency in both series with effect being more prominent in
1H-series with compound 315 being more potent than unsubsti-
tuted 312. This effect of methyl substitution at position 6 seems
Table 34
In vitro screening of compounds 318 and 319 against recombinant 5-reductase I
and II expressed in CHO cells.
IC
50
(nM)
Type II 5-reductase, IC
50
(nM)
318
a
582.1 No inhibition
319 20,000400 No inhibtion
a
Mixture of
6a(10a)
/
10(10a)
isomers in 10:1 ratio.
consistent with the observation that the introduction of the same
group on the corresponding position 7 in 4-azasteroids increased
their 5-reductase I selectivity [70]. Presence of methyl group at
position 5 found to decrease the potency of the compounds while
introduction of methyl at position 1 as in compound 317 caused
only a slight decrease in activity when compared to unsubstituted
compound 312.
In 2001, Guarna et al. studied the effect of C-ring modications
in benzo[c]quinolizin-3-ones. They synthesized several octahydro-
and decahydrobenzo[c]quinolizin-3-one derivatives containing
partially or fully saturated C-ring. These compounds were found
to be selective 5-reductase I inhibitors. Benzo[c]quinolizin-3-one
inhibitor lacking the aromatic C-ring but with a double bond at
6a10a 318 displayed an inhibitory potency 345-fold higher than
that of the corresponding 6a10a saturated, trans-fused compound
319 (Table 34) [192].
A 3D-QSAR model correlating the potency of the inhibitors with
their physicochemical features using density functional theory
(DFT) was also developed for a series of benzo[c]quinolizin-3-ones
derivatives byaddingtwononstandard variables (dipolemoment
and log P) to the classical electrostatic and steric comparative
molecular eld analysis (CoMFA) elds [193].
With the aim to discover new dual non-steroidal inhibitors of
5-reductase I and II a series of benzo[c]quinolizin-3-ones deriva-
tives (320325) bearing diverse substituents at position 8 were
synthesized in 2005 [194]. They were tested towards 5-reductase
I and II expressed by Chinese Hamster Ovary cells (CHO 1827 and
CHO 1829), respectively. It was found out that most potent dual
inhibitors were obtained when F atom was introduced on the phe-
nol moiety of these esters. All compounds displayed inhibition
towards 5-reductase I in the range of 93165nM(Table 35). Com-
pound 322 was found to be the most potent dual inhibitor of the
series with IC
50
values about 100nM for both enzymes.
32. Non-steroidal aryl acids
Some novel 9,10-dihydrophenanthrene-2-carboxylic acids
(326328) were prepared by formally removing D-ring from
parent androstene carboxylic acid inhibitors and contrary to them,
were found to be selective 5-reductase I inhibitors. Introduction
of a bromine atom at position 7 in compound 328 gave the most
potent compound of the series. Substitution by chlorine at position
7 in compound 327 does not result in increase in potency as
compared to unsubstituted compound 326. These compounds are
supposed to interact with the positively charged enzymeNADP
+
complex in an uncompetitive manner versus testosterone [195].
Moreover when double bond was introduced in the B-ring as
in compound 329 (formally obtained by removing the D-ring from
Table 35
In vitro screening of compounds 320325 against recombinant 5-reductase I and
II expressed in CHO cells.
Compounds Type I 5-reductase (%
inhibition at 10M)
Type II 5-reductase (%
inhibition at 10M)
320 102 553
321 129 584
322 93 119
323 160 134
324 138 166
325 42 368
Table 36
Invitro screening of compounds 326330against recombinant human5-reductase
I and II.
Compounds Type I 5-reductase (K
i,app
)
(nM)
Type II 5-reductase
(K
i,app
) (nM)
326 315 >10,000
327 320 2,500
328 26 10,000
329 1200 260
330 1900 1,600
Epristeride 163) the selectivity toward 5-reductase I was found
to be lost in favor of an increased potency towards 5-reductase II
(Table 36) [196].
On removal of two or more rings fromthe parent steroidal com-
pounds several aryl acids mimics of steroidal carboxylic acids have
been synthesized (331336). Hartmann et al. synthesized several
N-substituted 4-(5-indolyl) benzoic acids but potent and selec-
tive human 5-reductase I inhibitors were not found from the
series. Only compound 331 with IC
50
value of 67nMagainst human
5-reductase I was the most potent inhibitor [197]. Similarly, com-
pound 332 was found to possess IC
50
value of 680nM [198].
Fig. 8. SAR of benzophenone series.
Igarashi et al. synthesized a new series of indole derivatives
as potent human prostatic 5-reductase inhibitors. Compounds
(333336) were found to be most potent among the series with
4-[(1-benzyl-1H-indol-5-yl) oxy]-3-chlorobenzoic acid 334 having
an IC
50
value of 0.44nMwhile 3-chloro-4-{1-(4-phenoxybenzoyl)-
1H-indol-5-yl]oxy}benzoic acid 335 showed inhibitory activities
for both human and rat prostatic 5-reductase with IC
50
values of
2.1 and 73nM, respectively [199].
Fig. 9. SAR of indole series.
Screening of aryl carboxylate versus the human 5-reductase
isozymes by SmithKline-Beecham company led to the discovery
of two series of selective and potent 5-reductase II non-steroidal
inhibitors based on benzophenone and indolecarboxylic acids
skeleton. In benzophenone series of inhibitors the linker between
the A- and B-rings proved to be crucial whereas linker between
B- and C-rings was more tolerant of variation. Both the A-ring
carboxylic acid and C-ring are critical for activity. Compounds 337
and 338 were found to be most potent among the series with
K
i,app
being 10 and 5nM, respectively. In indole series there was
a strong preference for substitution at the 5- or 6-position of the
indole ring. Compounds 339 and 340 were most active among the
series with K
i,app
being 10 and 40nM, respectively The structure
activity relationships of both the series are summarized as below
(Figs. 8 and 9) [43,200].
Takami et al. synthesized various indole derivatives with
varied substituents on the ,-unsaturated double bond
and evaluated them for activity to inhibit rat prostatic
5-reductase. Among the various derivatives they found
that (Z)-4-{2-[[3-[1-(4,4
-diuorobenzhydryl)indol-5-yl]-2-
pentenoyl]-amino]phenoxy}butyric acid (341,KF20405) was the
most potent compound having activity about 20 times greater
than Finasteride (13) and an IC
50
value of 0.480.086nM [201].
A novel series of indole and benzimidazole derivatives were
also synthesized and evaluated for their inhibitory activity
of rat prostatic 5-reductase. Among the series, 4-{2-[1-(4,4
-
dipropylbenzhydryl)indole-5-carboxamido]phenoxy}butyric acid
(342) and its benzimidazole analogue (343) showed potent
inhibitory activities with IC
50
values of 9.61.0 and 131.5nM,
respectively [202].
Sawada et al. synthesized a novel series of indolizinebutyric
acids with various benzoyl substituents.FK687 (344) (S)-4-[1-[4-
[[1-(4-isobutylphenyl) butyl] oxy] benzoyl] indolizin -3-yl] butyric
acid displayed strongest in vitro inhibitory activity (IC
50
=4.6nM)
against the human enzyme and in vivo inhibitory activity
(IC
50
=1.7nM) against the castrated young rat model among the
series [203].
In 2002, various N-substituted 4
-biphenyl-4-carboxylic acids
were synthesizedby increasing the conformational exibility using
an ether linker between the steroidal AC-ring mimetics and were
tested against human and rat 5-reductase type I and type II. Two
compounds were found to be most potent with compound 345
showing an IC
50
value of 60nM while 346 showed an IC
50
value
improved by a factor of 5 from 1.9 to 0.38M in comparison with
the parent biphenyl compound 347 [204].
Baston et al. synthesized several 3,4-dihydro-naphthalene-2-
carboxylic acids and evaluated them for 5-reductase inhibitory
activity. The most active inhibitors were 6-[3-(N,N-dicyclohexyl
aminocarbonyl) phenyl]-3,4-dihydro-naphthalene-2-carboxylic
acid (348) (IC
50
=0.75M, human type II; IC
50
=0.81M, human
type I) and 6-[4-(N,N-diisopropylamino-carbonyl) phenyl]
naphthalene-2-carboxylic acid (349) (IC
50
=0.2M, human
type II). The latter compound was shown to deactivate the enzyme
in an uncompetitive manner (K
i
=90nM; K
m
, T =0.81.0M)
similar to the steroidal inhibitor Epristeride (163) [205].
Novel substituted benzoyl benzoic acids and phenylacetic acids
were synthesized by Salem et al. based on the template structure
338 and were evaluated for the inhibition of rat and human steroid
5-reductase isozymes I and II. The phenylacetic acid derivatives
were more potent thanthe analogous benzoic acids. Brominationin
the 4-position of the phenoxy moiety led to the strongest inhibitor
of the series against human 5-reductase II (352; IC
50
=5nM),
which was equipotent to Finasteride (13) while compounds 350
(IC
50
=23nM) and 351 (IC
50
=27nM) were also found to potent
inhibitors against 5-reductase type II [206].
Kato and coworkers synthesized a series of pyrrole butyric acid
derivatives and evaluated them for inhibitory activity on human
and rat steroid 5-reductase. In case of para-aminobenzoyl pyrrole
derivatives (353356), the introduction of ethyl (354) or isopropyl
(355) at C-4 increased the activity [IC
50
being 32 and 9.2, respec-
tively], whereas the replacement with carboxyl (356) resulted
in compounds with decreased inhibitory activity against human
5-reductase enzyme, indicating steric restriction in the binding
site of the enzyme. Compound with m-amino benzyl pyrrole (357)
moiety was found to be more active than the corresponding para
isomer (355) [IC
50
=3.2nM].
Compound 358, having 2-hexyloctylamino group, was found to
be most potent inhibitor among the compounds with IC
50
being
0.60nM against human and 5.8nM against rat 5-reductase [207].
A novel series of indole-3-alkanoic acids with varied N-benzyl
substituents were also synthesized. Amongst these 4-[1-(6,6-
dimethyl-6H-dibenzo [b,d] pyran-3-yl) methyl indol-3-yl]-butyric
acid(359; FR119680) displayedveryhighinhibitoryactivityagainst
rat prostatic 5-reductase (IC
50
=5.0nM) [208].
Igarashi et al. found a novel series of phenoxybenzoic acids
derivatives as potent inhibitors of human prostatic 5-reductase.
It was found that introduction of a chloro (360), uoro (361) or
methoxy (362) groupat 3-positionof benzene ring (R
1
) leads to for-
mation of compounds with high inhibitory activity with IC
50
being
0.87, 0.67 and 0.56nM, respectively [209].
A series of indoline and aniline derivatives have also been
synthesized so as to inhibit both human and rat prostatic
5-reductase. Among the indoline series, 3-chloro-4-{[1-(4-
phenoxybenzyl)indolin-5-yl]oxy}benzoic acid (363; YM-36117)
was found to be the most potent inhibitor against human enzyme
having an IC
50
value of 5.3 and 46nMagainst the rat enzyme while
in aniline series, 3-chloro-4-{4-[N-(4-phenoxybenzyl)amino] phe-
noxy}benzoic acid (364) turned out to be most potent inhibitor
with an IC
50
against human and rat enzyme as 10 and 5.5nM,
respectively [210].
33. Bisubstrate inhibitors
Ishibashi et al. synthesized a series of novel benzofuran deriva-
tives with both carboxy and 5- or 6-diphenylmethylcarbamoyl
groups and their inhibitory activities against rat and human testos-
terone5-reductaseweretestedinvitro. Thederivatives weremore
active against human type I enzyme than against type II enzyme.
The 6-carbamoyl derivative such as 365 tended to be more potent
than the 5-carbamoyl ones such as 366 with 365 being the most
potent compound having IC
50
value of 37.9, 50 and 340nMagainst
rat, human type I and human type II isozymes [211].
Later, they also synthesized a series of 2-phenylbenzofuran
derivatives with a carbamoyl, alkylamino, or alkyloxy group at
the 5 or 6 position of the benzofuran ring. It was found that
carbamoyl derivatives had more potent inhibitory activities than
the alkylamino or alkyloxy derivatives against the rat enzyme and
the 6-carbamoyl derivatives tended to be more potent than the
5-carbamoyl ones. The 6-carbamoyl and 6-alkylamino derivatives
were found to be more potent inhibitors against human type I
enzyme than type II but on whole compounds were found not to
be selective [212]. The non-steroidal o-hydroxyaniline (261; ONO-
3805) was a weak compound in vitro versus human 5-reductase
II. It is a bi-substrate inhibitor in which the butanoic acid moiety
is thought to be localized in the region of the phosphate group of
NADPH and the lipophilic part could be orientated in the region
of the steroidal C and D-ring, thus occupying the hydrophobic
pocket of the enzyme. The fact that this compound acts as non-
competitive inhibitor (versus T) and not as uncompetitive one,
supports this hypothesis [173,213,214]. This prompted Pzer to
prepare the derivatives of 261 and subsequently C-3 acylindole
(367) was prepared which had improved potency versus both
human 5-reductase enzymes. The benzodioxolane (368) adopts
a similar minimum conformation to the ether (367) and proved
to be a potent dual inhibitor of both 5-reductase enzymes.
In common with the steroidal carboxylic acid inhibitors, these
compounds require the carboxylic acid moiety for potency and
the 3-acylindole motif was found to be crucial for dual activity
presumably by allowing access to both the conformations 369
and 370. The corresponding 2-methyl analog 371 which adopts
conformation 370 due to the presence of methyl group on the
Table 37
In vitro screening of compounds 367371 against human 5-reductase I and II and
rat 5-reductase.
Compounds Rat 5-reductase,
IC
50
(nM)
Human type I
5-reductase, IC
50
(nM)
Human type II
5-reductase, IC
50
(nM)
367 1 40 4
368 9 25 23
371 588 10 6300
ONO-3805 (225) 1.7 256
indole ring was found to be a selective inhibitor of 5-reductase
I (Table 37) [215]. FK-143 (372) 4-[3-[3-[bis (4-isobutylphenyl)
methyl amino] benzoyl]-lH-indol-l-yl] butyric acid was disclosed
by Sawada et al. as a potent dual inhibitor of both human 5-
reductase isozymes. It inhibited in vitro human and rat prostatic
5-reductase in a dose-dependent manner with an IC
50
of 1.9
and 4.2nM, respectively, in a non-competitive fashion while in
vivo showed potent inhibitory activity against castrated young rat
model. This compound can be a potential drug for the treatment of
benign prostatic hyperplasia [216218].
34. Miscellaneous non-steroidal inhibitors
In search of novel non-steroidal mimics of steroidal inhibitors
of 5-reductase, 4-(2-phenylethyl)cyclohex-1-enecarboxylic acids
were synthesized with different substituents in para position of
the phenyl ring such as N,N-diisopropylcarbamoyl (373), phenyl,
phenoxy, etc. They turned out to be good inhibitors of the human
prostatic 5-reductase isozyme II with 373 being the most potent
one (IC
50
=760nM) [219].
Fan et al. evaluated a series of umbelliferone (7-
hydroxycoumarin) derivatives as inhibitors of 5-reductase I on
LNCaP cells. The coumarin skeleton was considered as a mimetic of
the proposed transition state of the natural substrate and as well
as bioisostere of quinolin-2-one 1
,1
-dimethylallyloxycoumarin
(374) showed potent inhibitory activity (IC
50
=1.3M) for the
5-reductase I. This was possibly a result of conformational effects
of geminal dimethyl group. 8-Allyl-7-hydroxycoumarin (375) also
exhibited potent inhibitory activity (IC
50
=0.99M) against 5-
reductase I enzyme. Introduction of a carbonyl group at 7-position
(376) resulted in only a slight increase in 5-reductase I inhibitory
activity (IC
50
=0.49M) [220].
Due to the excellent estrogen receptor binding afnity of a
series of 2
,6
-disubstituted 4-hydroxy-4
-hydroxymethyl biphenyl
derivatives Lesuisse et al. designed various biphenyls as surrogates
of the steroidal backbone. They hypothesized that by introducing
appropriate substituents non-steroidal estrogens could be tai-
lored into 5-reductase inhibitors. Two compounds (377 and 378)
emerged as potent type II 5-reductase inhibitors with IC
50
being
71 and 9.8nM, respectively [221].
Chen et al. evaluated isoavonoids as potential non-steroidal
inhibitors of rat 5-reductase by using the hypothetical phar-
macophore of 5-reductase. They proposed that although these
compounds (379382) were inhibitors of rat 5-reductase in the
range of 2749Mthey couldbe evaluatedas human5-reductase
inhibitors [222].
Hasoda et al. in 2007 designed and synthesized novel type
I 5-reductase inhibitors by using 3,3-diphenylpentane skeleton
as a substitute for the usual steroid skeleton. 4-(3-(4-(N-
Methylacetamido) phenyl) pentan-3-yl) phenyldibenzylcarbamate
(383) was found to be a competitive 5-reductase type I inhibitor
with the IC
50
value of 0.84M among the series [223].
35. Conclusion and future ahead
Finasteride (13) and Dutasteride (27) are the only two steroidal
clinically used drugs that have evolved from nearly 40 years of
research on steroids as 5-reductase inhibitors but many com-
pounds have shown promising results such as Epristeride (163)
which is in clinical trials. Combination therapy of 5-reductase
inhibitors withvarious -blockers liketerazosin, alfuzosinanddox-
azosin has been highly successful in the management of benign
prostatic hyperplasia and combinations of 5-reductase inhibitors
with anti-inammatory agents have been tried successfully and it
is expected that this trend will continue. But the most challenging
work will be the purication of 5-reductase, for which all efforts
have failed so far because of the unstable nature of the enzyme
during purication, leading to a loss of activity. Ligand-based com-
parative pharmacophore development using the known potent
inhibitors couldprovide aninsight into the structural requirements
for the possible inhibitors of 5-reductase [224]. Data obtained
by such techniques could be used for developing more potent
and selective inhibitors that can be manufactured by pharma-
ceutical industries at a lower cost. Meanwhile, various classes of
non-steroidal inhibitors have also emerged. It would be encour-
aging to see if any of these molecules such as FK-143 (372) will be
availablefor clinical use. Meanwhile, synthesis of steroidal andnon-
steroidal derivatives will continue in search of a more potent and
less toxic inhibitor of 5-reductase. The basic research described
in this review article will assist in this process.
Acknowledgements
Authors Saurabh Aggarwal and Abhilasha Verma gratefully
acknowledge University Grants Commission (UGC, New Delhi,
India) for providing fellowship to carry out research work.
References
[1] Tiwari A, Krishna NS, Nanda K, Chugh A. Benign prostatic hyperplasia: an
insight into current investigational medical therapies. Exp Opin Invest Drugs
2005;14:135972.
[2] Hieble JP. Therapeutic strategies for benign prostatic hypertrophy. Drug Dis-
cov Today Ther Strat 2004;1:2438.
[3] Kulig K, Malawska B. Trends in the development of new drugs for treatment
of benign prostatic hyperplasia. Curr Med Chem 2006;13:3395416.
[4] Dull P, Reagan Jr RW, Bahnson RR. Managing benign prostatic hyperplasia.
Am Fam Physician 2002;66:7784.
[5] Rassweiler J, Teber D, Kuntz R, Hofmann R. Complications of transuretheral
resection of the prostate (TURP)-incidence, management and prevention. Eur
Urol 2006;50:96980.
[6] Fitzpatrick JM, Artibani W. Therapeutic strategies for managing BPHprogres-
sion. Eur Urol Suppl 2006;5:9971003.
[7] Reid P, Kantoff P, Oh W. Antiandrogens in prostate cancer. Invest New Drugs
1999;17:27184.
[8] Li X, Chen C, Singh SM, Labrie F. The enzyme and inhibitors of 4-ene-3-
oxosteroid 5-oxidoreductase. Steroids 1995;60:43041.
[9] Flores E, Bratoeff E, Cabeza M, Ramirez E, Quiroz A, Hueze I. Steroid 5-
reductase inhibitors. Mini Rev Med Chem 2003;3:22537.
[10] Tarter TH, Vaughan Jr ED. Inhibitors of 5-reductase in the treatment of
benign prostatic hyperplasia. Curr Pharm Des 2006;12:77583.
[11] KyprianouN, Isaacs JT. Quantal relationshipbetweenprostatic dihydrotestos-
terone and prostatic cell content: critical threshold concept. Prostate
1987;11:4150.
[12] Mckeehan WL. Growth factor receptors and prostate cell growth. Cancer Surv
1991;11:16575.
[13] Lee C. Role of androgen in prostate growth and regression: stromalepithelial
interaction. Prostate Suppl 1996;6:526.
[14] Carson III C, Rittmaster R. The role of dihydrotestosterone in benign prostatic
hyperplasia. Urology 2003;61:27.
[15] Rubin BL, Dorfman RI. In vitro conversion of testosterone to 17-
hydroxyandrostan-3-one. Proc Soc Exp Biol Med 1956;91:5856.
[16] Abul-Hajj YJ. Stereospecicity of hydrogen transfer from NADPH by steroid
4
-5- and
4
-5-reductase. Steroids 1972;20:21522.
[17] Russell DW, Wilson JD. Steroid 5-reductase: two genes/two enzymes. Annu
Rev Biochem 1994;63:2561.
[18] Bjrkhem I. Mechanism and stereochemistry of the enzymatic conver-
sion of a
4
-3-oxosteroid into a 3-oxo-5-steroid. Eur J Biochem 1969;8:
34551.
[19] Holland HL, Xu W, Hughes DW. Stereochemistry of reduction by the 5-
reductase enzyme of Penicillium decumbens and the
1
H NMR assignment of
5-dihydrotestosterone. J Chem Soc Chem Commun 1989:17602.
[20] Andersson S, Russell DW. Structural and biochemical properties of cloned
and expressed human and rat steroid 5-reductases. Proc Natl Acad Sci USA
1990;87:36404.
[21] Labrie F, Sugimoto Y, Luu-The V, Simard J, Lachance Y, Bachvarov D,
et al. Structure of human type II 5-reductase gene. Endocrinology
1992;131:15713.
[22] Wilson JD, Grifn JE, Russell DW. Steroid 5-reductase 2 deciency. Endocr
Rev 1993;14:57793.
[23] Andersson S, Berman DM, Jenkins EP, Russell DW. Deletion of steroid 5-
reductase 2gene inmale pseudohermaphroditism. Nature 1991;354:15961.
[24] Poletti Angelo, Coscarella A, Negri-Cesi P, Colciago A, Celotti F, Mar-
tini L. 5-Reductase isozymes in the central nervous system. Steroids
1998;63(56):24651.
[25] Jenkins EP, Hsieh CL, Milatovich A, Normington K, Berman DM, Francke U,
et al. Characterization and chromosomal mapping of a human steroid 5-
reductase gene and pseudogene and mapping of the mouse homologue.
Genomics 1991;11:110212.
[26] Tamura K, Furihata M, Tsunoda T, Ashida S, Takata R, Obara W, et al. Molecular
features of hormone-refractory prostate cancer cells by genome-wide gene
expression proles. Cancer Res 2007;67:511725.
[27] Uemura M, Tamura K, Chung S, Honma S, Okuyama A, Nakamura Y, et al. Novel
5 alpha-steroid reductase (SRD5a3, type-3) is overexpressed in hormone-
refractory prostate cancer. Cancer Sci 2008;99:816.
[28] Kazutoshi Y, Labrie F, Luu-The V. Type 3 5-alpha-reductase is an ubiquitous
enzyme highly expressed in the brain and strongly inhibited by nasteride
and dutasteride. In: 13th international congress on hormonal steroids and
hormones and cancer, vol. 53. 2008. p. 107.
[29] SinghH, Parashar VV, PadmanabhanS, Mathur RB. Azasteroids: syntheses and
signicance. Indian J Pharm Educ 1970;4:220.
[30] Singh H, Jindal DP, Yadav MR, Kumar M. Heterosteroids and drug research.
Prog Med Chem 1991;28:233300.
[31] Alauddin M, Martin-Smith M. Biological activity in steroids possessing nitro-
gen atoms. II. Steroidal alkaloids. J Pharm Pharmacol 1962;14:46995.
[32] Doorenbos NJ, Wu MT. Steroids. III. Synthesis of some 3-aza-A-
homocholestanes by the Beckmann and Schmidt rearrangements in
polyphosphoric acid. J Org Chem 1961;26:25489.
[33] Mazur RH. Azasteroids. III. 3-Aza-A-homo androgens. J Org Chem
1962;28:24850.
[34] Anderson K, Liao S. Selective retention of dihydrotestosterone by prostatic
nuclei. Nature 1968;219(5151):2779.
[35] Haffner C. An efcient synthesis of 3-pyridyl N-oxide steroids: inhibitors of
5-reductase. Tetrahedron Lett 1994;35:134952.
[36] RobinsonAJ, DeLucca I, DrummondS, Boswell GA. Steroidal nitrone inhibitors
of 5-reductase. Tetrahedron Lett 2003;44:48014.
[37] Voigt W, Fernandez EP, Hsia SL. Transformation of testosterone into 17-
hydroxy-5-androstan-3-one by microsomal preparations of human skin. J
Biol Chem 1970;245:55949.
[38] Voigt W, Hsia SL. Further studies ontestosterone 5-reductase of humanskin.
Structural features of steroid inhibitors. J Biol Chem 1973;248:42805.
[39] Rasmusson GH, Johnston DBR, Reinhold DF, Utne T, Jobson RB. Prepara-
tion of 4-aza-17-substituted-5-androstan-3-ones useful as 5-reductase
inhibitors. International Patent Application U.S. 4,220,775 (1980).
[40] Rasmusson GH, Johnston DBR, Arth GE. 4-Aza-17-substituted 5-
androstan-3-one reductase inhibitors. International Patent Application U.S.
4,377,584 (1983).
[41] Rasmusson GH, Reynolds GF, Utne T, Jobson RB, Primka RL, Brooks
JRB. Azasteroids as inhibitors of rat prostatic 5-reductase. J Med Chem
1984;27:1690701.
[42] Rasmusson GH, Reynolds GF, Steinberg NG, Walton E, Patel GF, Liang T, et al.
Azasteroids: structureactivity relationships for inhibition of 5-reductase
and of androgen receptor binding. J Med Chem 1986;29:2298315.
[43] Kenny B, Ballard S, Blagg J, Fox D. Pharmacological options in the treatment
of benign prostatic hyperplasia. J Med Chem 1997;40(9):1293313.
[44] Witzel BE, Tolman RL, Rasmusson GH, Bakshi RK, Yang SS. Preparation of
17-ethers and thioethers of 4-azasteroids as 5-reductase inhibitors. U.S.
5,536,727 (1996), to Merck and Co., Inc., USA.
[45] Durette PL, Hagmann W, Rasmusson GH, Tolman RL, Kopka IE, Sahoo SP,
et al. 16-Substituted-4-aza-3-oxo-androstane as 5-reductase isozyme 1
inhibitors. U.S. 5,739,137 (1998), to Merck and Co., Inc., USA.
[46] Harris G, Tolman RL, Sahoo SP. Preparation of 17-alkyl-7-substituted-4-
azasteroid derivatives as 5-reductase inhibitors. U.S. 5,763,361 (1998), to
Merck and Co., Inc., USA.
[47] Tan CH, Fong CY, Chan WK. The inhibition of 3 beta HSD activity in porcine
granulosa cells by 4-MA a potent 5-reductase inhibitor. Biochem Biophys
Res Commun 1987;144:16671.
[48] Brandt M, Levy MA. 3-Hydroxy-
5
-steroid dehydrogenase/3-keto-
5
-
isomerase from bovine adrenals: mechanism of inhibition by 3-oxo-4-aza
steroids and kinetic mechanism of the dehydrogenase. Biochemistry
1989;28:1408.
[49] McConnell JD. Androgen ablation and blockade in the treatment of benign
prostatic hyperplasia. Urol Clin North Am 1990;17:66170.
[50] Faller B, Farley D, Nick H. Finasteride: a slow-binding 5-reductase inhibitor.
Biochemistry 1993;32:570510.
[51] Vaughan D, Imperato-McGinley J, McConnell J, Matsumoto AM, Bracken B,
Roy J, et al. Long-term (78 years) experience with nasteride in men with
benign prostatic hyperplasia. Urology 2002;60:10404.
[52] Bull HG, Garcia-Calvo M, Andersson S, Baginsky WF, Chan HK, Ellsworth DE,
et al. Mechanism-based inhibition of human steriod 5-reductase by Finas-
teride: enzyme-catalyzed formation of NADP-dihydronasteride, a potent
bisubstrate analog inhibitor. J Am Chem Soc 1996;118:235965.
[53] Moss ML, Kuzmic JP, Stuart D, Tian G, Peranteau AG, Frye SV, et al. Inhi-
bition of human steroid 5-reductases type I and II by 6-aza-steriods:
structural determinants of one-step vs two-step mechanism. Biochemistry
1996;35:345764.
[54] Harris GS, Kozarich JW. Steroid 5-reductase inhibitors in androgen-
dependent disorders. Curr Opin Chem Biol 1997;1:2549.
[55] Weintraub PM, Blohm TR, Laughlin M. Preparation of 20-(hydroxymethyl)-
4-methyl-4-aza-2-oxa-5-pregnan-3-one as an inhibitor of testosterone 5-
reductase. J Med Chem 1985;28(6):8313.
[56] Bakshi RK, Rasmusson GH, Patel GH, Mosely RC, Chang B, Ellsworth K, et al.
4-Aza-3-oxo-5-androst-1-ene-17-N-aryl-carboxamides as dual inhibitors
of human type 1 and type 2 steroid 5-reductases. Dramatic effect of N-aryl
substituents on type 1 and type 2 5-reductase inhibitory potency. J Med
Chem 1995;38:318992.
[57] Roehrborn CG, Boyle P, Nickel JC, Hoefner K, Andriole G. Efcacy and safety of
a dual inhibitor of 5-alpha-reductase types 1 and 2 (dutasteride) in men with
benign prostatic hyperplasia. Urology 2002;60(3):43441.
[58] Stuart JD, Lee FW, Simpson ND, Kadwell SH, Overton LK, Hoffman CR, et
al. Pharmacokinetic parameters and mechanisms of inhibition of rat type
1 and 2 steroid 5-reductases: determinants for different in vivo activi-
ties of GI198745 and nasteride in the rat. Biochem Pharmacol 2001;62:
93342.
[59] Evans HC, Goa KL. Dutasteride. Drugs Aging 2003;20(12):90516.
[60] Clark RV, Hermann DJ, Cunningham GR, Wilson TH, Morrill BB, Hobbs
S. Marked suppression of DHT in men with benign prostatic hyperplasia
by dutasteride, a dual 5-reductase inhibitor. J Clin Endocrinol Metabol
2004;89:217984.
[61] Schulman C, Pommerville P, Hofner K, Wachs B. Long-term therapy with
the dual 5-reductase inhibitor dutasteride is well tolerated in men with
symptomatic BPH. BJU Int 2006;97(1):7380.
[62] Brown CT, Nuttall MC. Dutasteride: a new 5-reductase inhibitor for men
withlower urinarytract symptoms secondarytobenignprostatic hyperplasia.
Int J Clin Pract 2003;57(8):7059.
[63] Clark RV, Hermann DJ, Cunningham GR, Wilson TH, Morrill BB, Hobbs S.
Marked suppression of dihydrotestosterone in men with benign prostatic
hyperplasia by dutasteride, a dual 5-reductase inhibitor. J Clin Endocrinol
Metab 2004;89(5):217984.
[64] Djavan B, Milani S, Fong YK. Dutasteride: a novel dual inhibitor of 5-
reductase for benign prostatic hyperplasia. Expert Opin Pharmacother
2005;6:3117.
[65] Andriole GL, Kirby R. Safety andtolerability of the dual 5-reductase inhibitor
dutasteride in the treatment of benign prostatic hyperplasia. Eur Urol
2003;44:828.
[66] Salle DE, Briatico G, Giudici D, Ornati G, Nesi M, Panzeri A. 17-Acylurea
derivatives of 4-azasteroids as inhibitors of testosterone 5-reductase. J
Steroid Biochem Mol Biol 1992;41:7658.
[67] Salle DE, Briatico G, Giudici D, Ornati G, Panzeri A. Endocrine properties of
the testosterone 5-reductase inhibitor Turosteride (FCE 26073). J Steroid
Biochem Mol Biol 1994;48:2418.
[68] Lourdusamy M, Cote J, Laplante S, Labrie F, Singh SM. Synthesis and
in vitro study of 17-[N-ureylene-N,N
-disubstituted]-4-methyl-4-aza-5-
androstan-3-ones as selective inhibitors of type I 5-reductase. Bioorg Med
Chem Lett 1993;5:3059.
[69] Li X, Singh SM, Labrie F. Synthesis and in vitro activity of 17-(N-alkyl
/arylformamido)- and 17-[(N-alkyl/aryl)alkyl/arylamido]-4-methyl-4-aza-
3-oxo-5-androstan-3-ones as inhibitors of human 5-reductases and
antagonists of the androgen receptor. J Med Chem 1995;38:115873.
[70] Bakshi RK, Patel GF, Rasmusson GH, Baginsky WF, Cimis G, Ellsworth
K, et al. 4,7-Dimethyl-4-azacholestan-3-one (MK-386) and related 4-
azasteroids as selective inhibitors of human type 1 5-reductase. J Med Chem
1994;37:38714.
[71] Ellsworth K, Azzolina B, Baginsky W, Bull H, Chang B, Cimis G, et al. MK386:
a potent, selective inhibitor of the human type I 5-reductase. J Steroid
Biochem Mol Biol 1996;58(40):37784.
[72] Li X, SinghSM, LourdusamyM, MerandY, VeilleuxR, Labrie F. Synthesis andin
vitro antiandrogenic activity of 17-hydroxy-17-(-hydroxy/haloalkyn-l-
yl)-4-methyl-4-aza-3-oxo-5-androstan-(1-ene)-3-ones. Bioorg Med Chem
Lett 1995;5(10):10614.
[73] Salle ED, Giudici D, Biagini L, Cominato C, Briatico G, Panzeri A. Effects of 5-
reductase inhibitors on intraprostatic androgens in the rat. J Steroid Biochem
Mol Biol 1995;53(16):3815.
[74] Salle ED, Briatico G, Ornati G, Zaccheo T, Buzzetti F, Nesi M, et al.
Novel aromatase and 5-reductase inhibitors. J Steroid Biochem Mol Biol
1994;49(46):28994.
[75] Labrie F, Merand YM, SinghSM. Inhibitors of testosterone 5-reductase activ-
ity. PCT Int Appl 1993:90 [Endorecherche Inc., Can.].
[76] Panzeri A, Nesi M, Di SE. 17-Substituted 4-aza-5-androstan-3-one deriva-
tives useful as testosterone 5-reductase inhibitors, and their preparation,
compositions, and use. PCT Int Appl 1994:70 [Farmitalia Carlo Erba S.R.L.,
Italy].
[77] Giudici D, Briatico G, Cominato C, Zaccheo T, Iehle C, Nesi M, et al. FCE 28260,
a new 5-reductase inhibitor: in vitro and in vivo effects. J Steroid Biochem
Mol Biol 1996;58(3):299305.
[78] Hausler A, Allegrini PR, Biollaz M, Batzl C, Scheidegger E, Bhatnagar AS.
CGP53153: a new potent inhibitor of 5-reductase. J Steroid Biochem Mol
Biol 1996;57(3/4):18795.
[79] Ishibashi K, Kurata H, Hamada T, Horikoshi H, Kojima K. Synthesis and
testosterone 5-reductase inhibitory activity of 11-substituted 4-aza-5-
androstane compounds. Eur J Med Chem 1996;31:67581.
[80] Tolman RL, Sahoo SP, Bakshi RK, Gratale D, Patel G, Patel S, et al. 4-Methyl-
3-oxo-4-aza-5-androst-1-ene-17-N-aryl-carboxamides: an approach to
combined androgen blockade [5-reductase inhibition with androgen recep-
tor binding in vitro]. J Steroid Biochem Mol Biol 1997;60(56):3039.
[81] Salle ED, Giudici D, Radice A, Zaccheo T, Ornati G, Nesi M, et al. PNU 157706,
a novel dual type I and II 5-reductase inhibitor. J Steroid Biochem Mol Biol
1998;64(34):17986.
[82] Hasserodt J, Janda KD, Lerner RA. A class of 4-aza-lithocholic acid-derived
haptens for the generation of catalytic antibodies with steroid synthase capa-
bilities. Bioorg Med Chem 2000;8(5):9951003.
[83] Menzenbach B, Droescher P, Hillisch A, Elger W, Schweikert HU, Schoellkopf
K. PCT Int Appl 2003:29.
[84] Frye SV, Haffner CD, Maloney PR, Mook RJ, Dorsey GF, Hiner RN, et
al. 6-Azasteriods: structureactivity relationships for inhibition of type 1
and 2 human 5-reductase and human adrenal 3-hydroxy-
5
-steroid
dehydrogenase/3-keto-
5
-steroidisomerase. J MedChem1994;37:235260.
[85] Frye SV, Haffner CD, Maloney RJ, Dorsey GF, Noe RA, Hiner RN, et al.
Structureactivity relationships for inhibition of type 1 and 2 human
5-reductase and human adrenal 3-hydroxy-
5
-steroid dehydrogenase/3-
keto-
5
-steroid isomerase by 6-aza-androst-4-en-3-ones: optimization of
the C17 substituent. J Med Chem 1995;38:26217.
[86] Patrick RM, Francis GF. Synthesis of a B-homo-6-azaandrost-4-ene-
3-one as a novel steroidal 5-reductase inhibitor. Tetrahedron Lett
1994;35(18):28236.
[87] Bergmann JP, Graham DW, Rasmusson GH, Tolmann, RL, Langen DV. 7-
Substituted -4-6-azasteroid derivatives as 5-reductase inhibitors. U.S.
5,438,061 (1995).
[88] Haffner C. Synthesis of 6-azacholesten-3-ones: potent inhibitors of 5-
reductase. Tetrahedron Lett 1995;36(23):403942.
[89] Fang FG, Sharp MJ. Synthesis of 6-aza androstenones. PCT Int Appl
1996:48.
[90] Aster SD, Graham DW, Langen DV. 16-Substituted-6aza-androsten-4-en-3-
ones as 5-reductase inhibitors. PCT Int Appl 1997:45.
[91] Rahier A, Taton M. Sterol biosynthesis: strong inhibition of maize
5,7
-sterol
7
-reductase by novel 6-aza-B-homosteroids and other analogues of a pre-
sumptive carbocationic intermediate of the reduction reaction. Biochemistry
1996;35(22):706976.
[92] Wenge X, Hairuo P, Leon HZ, Yu-Hua L, Cheng Z, Garth P, et al. 3-Hydroxy-
6-aza-cholestane and related analogues as phosphatidylinositol specic
phospholipaseC(PI-PLC) inhibitors withantitumor activity. BioorgMedChem
2000;8(4):699706.
[93] Xie W, Peng H, Kim DII, Kunkel M, Powis G, Zalkow LH. Structureactivity
relationship of aza-steroids as PI-PLC inhibitors. Bioorg Med Chem
2001;9(5):107383.
[94] Kasal A, Matyas L, Budesinsk M. Neurosteroid analogues: synthesis of 6-aza-
allopregnanolone. Tetrahedron 2005;61(9):226978.
[95] AhmadM, ShaullahI. Azasteroidfrom3-cholest-5-en-7-one. IndianJ Chem
1974;12:13234.
[96] Morzycki J, Sicinski R. Synthesis of 6,7-diazacholestane derivatives. Acta Chim
Hung 1985;120:23946.
[97] Rao HSP, Senthilkumar SP. Reviewon the synthesis of 8-azasteroids. Curr Org
Chem 2004;8(15):15218.
[98] Rahier A, Taton M, Schmitt P, Benviste P, Place P, Anding C. Inhi-
bition of
8
7
-sterol isomerase and of cycloeucalenolobtusifoliol
isomerase byN-benzyl-8-aza-4,10-dimethyl-transdecal-3-ol, ananalogue
of a carbocationic high energy intermediate. Phytochemistry 1985;24:
122332.
[99] Taton M, Benviste P, Rahier A. Inhibition of 2,3-oxidosqualene cyclase. Bio-
chemistry 1992;31:78928.
[100] Akers A, Ammermann E, Buschmann E, Gtz N, Himmele W, Lorenz G, et
al. Chemistry and biology of novel amine fungicides: attempts to improve
antifungal activity of fenpropimorph. Pestic Sci 1991;31:52138.
[101] Guarna A, Belle C, Machetti F, Occhiato EG, Payne AH, Cassiani C, et al. 19-Nor-
10-azasteroids: a novel class of inhibitors for human steroid 5-reductases 1
and 2. J Med Chem 1997;40:111229.
[102] Guarna A, Occhiato EG, Machetti F, Marrucci A, Danza G, Serio M, et al.
19-nor-10-azasteroids, a new class of steroid 5-reductase inhibitors. 2.
X-ray structure, molecular modeling, conformational analysis of 19-nor-10-
azasteroids and comparison with 4-azasteroids and 6-azasteroids. J Med
Chem 1997;40:346677.
[103] Murphy WI, Sarsam B, Ferguson G, Gallagher J. Azasteroids derived from
fusidic acid. J Chem Soc Perkin Trans 1998;1:41428.
[104] Scrapi D, Occhiato EG, Danza G, Serio M, Guarna A. Synthesis of 17-N-
substituted 19-nor-10-azasteroids as inhibitors of human 5-reductases I
and II. Bioorg Med Chem 2002;10:345561.
[105] Kutney JP, Vlattas IJ. Aza steroids. IV. Synthesis of 11-aza steroids in the preg-
nane series. Steroids 1964;4(5):595611.
[106] Cachoux F, Ibrahim-Ouali M, Santelli M. A new efcient synthesis of 11-aza
steroids. Tetrahedron Lett 2001;42(5):8435.
[107] Cachoux F, Ibrahim-Ouali M, Santelli M. Total synthesis of 11-azasteroids.
Synth Commun 2002;32(23):354960.
[108] Edwards O, Douglas J, Horwell D, Rank W, Sano T. Thermal andphotochemical
reaction of steroidal -azido ketones. Can J Chem 1992;70:240512.
[109] Lopez-Call E, Hoeer J, Eberbach W. Synthetic applications of conju-
gated nitrones: a novel entry to the 13-azasteroid system. Liebigs Ann
1996:185566.
[110] Barton D, Lusinchi X, Martinez Menndes A, Milliet P. Synthse paritelle
du chromophore steroidique aza-14a d-homo dine-8,14a prsent dans
lantibiotique A25822B. Tetrahedron 1983;39:22015.
[111] Chesnut R, Durham N, Brown R, Mawdsley E, Berlin K. Antibacterial activ-
ity of 15-azasteroids alone and in combination with antibiotics. Steroids
1976;27:52541.
[112] Dolle R, Allaudeen H, Kruse L. Design and synthesis of 14-methyl-15-aza-D-
homosterols as novel antimycotics. J Med Chem 1990;33:87780.
[113] Kierstead RW, Faraone A, Boris A. 16-Aza steroids. J Med Chem
1967;10:17781.
[114] Paquette LA, Fristad WE, Dime DS, Bailey TR. Silanes in organic synthesis.
8. Preparation of vinylsilanes from ketones and their regiospecic cyclopen-
tenone annulation. J Org Chem 1980;45:301728.
[115] Regan BM, Hayes FN. 17- and 17a-aza-D-homosteroids. J Am Chem Soc
1956;78:63943.
[116] SinghH, Chaudhary AK, Bhardwaj TR, Paul D. Neuromuscular blocking agents.
J Sci Ind Res 1984;43:30615.
[117] Jiang X, Wang J, Hu J, Ge Z, Hu Y, Hu H, et al. Synthesis of (5)-
17-azaandrostan-3-ols and (5)-17-aza-D-homoandrostan-3-ols and their
N-acylated derivatives. Steroids 2001;66(8):65562.
[118] Covey DF, Han M, Kumar AS, de la Cruz MAM, Meadows ES, Hu Y, et
al. Neurosteroid analogues. Structureactivity studies of N-acylated
17a-aza-D-homosteroid analogues of the anesthetic steroids (3, 5)-
and (3, 5)-3-hydroxypregnan-20-one. J Med Chem 2000;43(17):
32014.
[119] Wang C, Wang S, Xu Y, Hu Y, Hu H. Preparation of (5,13)-D-azasteroids
as key precursors of a new family of potential GABAA receptor modulators.
Steroids 2003;68:67783.
[120] Patrick G, Kinsman O. Synthesis and antifungal activity of novel aza-D-
homosteroids, hydroisoquinolines, pyridines and dihydropyridines. J Med
Chem 1996;31:61524.
[121] Andrianopoulos C, Stephanou G, Politi E, Demopoulos NA. Evaluation and
characterization of micronuclei induced by the antitumour agent ASE [3-
hydroxy-13- amino-13,17 seco-5-androstan-17-oic-13,17-lactam-p-bis
(2-chloroethyl) amino phenyl acetate] in human lymphocyte cultures. Muta-
genesis 2000;15(3):21521.
[122] Xenos C, Camoutis C. Synthesis of A- and D-homoazasteroidal isoxazoles. J
Heterocycl Chem 1999;36:13434.
[123] Gupta R, Pathak D, Jindal DP. Synthesis and biological activity of azasteroidal
[3,2-c]- and [17,16-c] pyrazoles. Eur J Med Chem 1996;31(3):2417.
[124] McDonald I, Nyce P, Muench DM, Gates CA, BlohmTR, Laughlin ME, et al. Inhi-
bition of steroid 5-reductase by inverted, competitive inhibitors. Bioorg
Med Chem Lett 1994;4:84751.
[125] Marcus PI, Talalay P. Induction and purication of - and -hydroxysteroid
dehydrogenases. J Biol Chem 1956;218:66174.
[126] Kashino S, Katz H, Glusker JP, Pollack RM, Bounds PL. Structures of 3-
and 17-oxirane inhibitors of 3-oxo-
5
-steroid isomerase. J Am Chem Soc
1987;109:676571.
[127] Murdock GL, Warren JC, Sweet F. Human placental estradiol 17-
dehydrogenase: evidence for inverted substrate orientation (wrong way
binding) at the active site. Biochemistry 1988;27:44528.
[128] Lopez-Call E, Hoeer J, Eberbach W. Synthetic applications of conju-
gated nitrones. A novel entry to the 13-azasteroid system. Liebigs Ann
1996:185566.
[129] Morzycki JW, Lotowski Z, Wilczewska AZ, Stuart JD. Synthesis of
4,17-diazasteroid inhibitors of human 5-reductase. Bioorg Med Chem
1996;4(8):120915.
[130] Gnds G, Gera L, Tth G, Klmn A, Bridson J. Synthesis and stereochem-
istry of 8,13-diaza-2,3-dimethoxygona-1,3,5(10),9(11)-tetraen-12-one and
-homo derivatives. Steroids 1998;63(78):37582.
[131] Sasaki K, Funabashi T, Ohtomo H, Nakayama T, Hirota T. Polycyclic
N-heterocyclic compounds. Synthesis and evaluation of anti-platelet
aggregation activity of 11,13,15-triazasteroid and related compounds. Het-
erocycles 1995;41(10):225162.
[132] Singh H, Gupta SK, Padmanablan DP, Bhardwaj TR. Steroids and related
studies. Part XXXVI. 7-17-diaza-7,17-dioxo-B,D-dihomo-5-androsten-3-
yl acetate. Indian J Chem 1977;15B:1012.
[133] Koutsourea AI, Arsenou ES, Fousteris MA, Nikolaropoulos SS. Synthetic
approaches for the synthesis of a cytostatic steroidal BD bilactam. Steroids
2003;68:65966.
[134] Trehan IR, Singh NP, Jain VK. A highly stereoselective synthesis of des-AB-
aromatic azasteroids. Indian J Chem 1995;34B:4846.
[135] Metcalf BW, Holt DA, Levy MA, Erb JM, Heaslip JI, Brandt M, et al. Potent
inhibition of human steroid 5(-reductase (EC 1.3.1.30) by 3-androstene-3-
carboxylic acids. Bioorg Chem 1989;17:3728.
[136] Levy MA, Brandt M, Heys R, Holt DA, Metcalf BW. Inhibition of rat liver
steroid 5-reductase by 3-androstene-3-carboxylic acids: mechanism of
enzymeinhibitor interaction. Biochemistry 1990;29:281524.
[137] Holt DA, Levy MA, Oh H-J, Erb JM, Heaslip JI, Brandt M, et al. Inhibition
of steroid 5-reductase by unsaturated 3-carboxy steroids. J Med Chem
1990;33:94350.
[138] Holt DA, Levy MA, Ladd DL, Oh H-J, Erb JM. Steroidal A ring aryl car-
boxylic acids: a new class of steroid 5-reductase inhibitors. J Med Chem
1990;33:93742.
[139] Holt DA, Levy MA, Yen H-K, Oh HJ, Metcalf BW, Weir PJ. Inhibition of steroid
5-reductase by 3-nitrosteroids: synthesis, mechanism of inhibition and in
vivo activity. Bioorg Med Chem Lett 1991;1:2732.
[140] Holt DA, Levy MA, Oh H-J, Metcalf BW. Synthesis of a steroidal A ring aro-
matic sulfonic acid as an inhibitor of steroid 5-reductase. Steroids 1991;56:
47.
[141] Holt DA, Levy MA, Ladd DL, Oh HJ, Erb JM, Heaslip JI, et al. 3-Phosphinic
acid and 3-phosphonic acid steroids as inhibitors of steroid 5-reductase:
species comparison and mechanistic studies. Bioorg Chem 1991;19:
24560.
[142] Blohm TR, Metcalf BW, Laughlin ME, Sjoerdsma A, Schatzma GL. Inhibition
of testosterone 5-reductase by a proposed enzyme-activated, active site-
directed inhibitor. Biochem Biophys Res Commun 1980;95:27380.
[143] Metcalf BW, Jund K, Burkhart JP. Synthesis of 3-keto-4-diazo-5-dihydro
steroids as potential irreversible inhibitors of steroid 5-reductase. Tetra-
hedron Lett 1980;21:158.
[144] Li X, Singh SM, Cote J, Laplante S, Vielleux R, Labrie F. Synthesis and in vitro
evaluation of 4-substituted N-(1,1-dimethylethyl)-3-oxo-4-androstene-
17-carboxamides as 5-reductase inhibitors and antiandrogens. J Med
Chem 1995;38:145661.
[145] Fei X-S, Tian W-S, Chen Q-Y. Synthesis of 4-triuoromethylsteroids: a
novel class of steroid 5-reductase inhibitors. Bioorg Med Chem Lett
1997;7:31138.
[146] Haase-Held M, Hatzis M, Mann J. The synthesis of 4-cyanoprogesterone: a
potent inhibitor of the enzyme 5-reductase. J Chem Soc Perkin Trans I
1992:29993000.
[147] Jarman M, Barrie SE, Houghton J, Rowlands MG, Mann J, Haase-Held M, et al.
Evaluation of some 4-uoro and 4-cyano derivatives of
4
-3-ketosteroids
as inhibitors of testosterone 5-reductase. J Enzyme Inhib Med Chem
1994;8:1723.
[148] Hartmann RW, Hector M, Haidar S, Ehmer PB, Reichert W, Jose J. Syn-
thesis and evaluation of novel steroidal oxime inhibitors of P450 17
(17-hydroxylase/C17-20-lyase) and5-reductasetypes 1and2. J MedChem
2003;43:426677.
[149] Wling J, Hackler L, Mernyk E, Schneider G, Tth I, Szcsi M, et al.
Neighbouring group participation. Part 15. Stereoselective synthesis of some
steroidal tetrahydrooxazin-2-ones, as novel presumed inhibitors of human
5-reductase. Steroids 2004;69:45160.
[150] Faredin I, Toth I, Wling J, Schneider G, Mesko E. In vitro inhibitory effects of
16-methyl-substituted steroids on 5-reductase in rat and human prostates.
Steroids 1994;59:56871.
[151] Sudo K, Yoshida K, Akinaga Y, Nakayama R. 5-Reduction of an anti-androgen
TSAA-291, 16-ethyl-17-hydroxy-4-estren-3-one, by nuclear 5-reductase
in rat prostates. Steroids 1981;38:5571.
[152] Dupuy GM, Roberts KD, Bleau G, Chapdelaine A. Steroidal inhibitors of
prostatic 5-reductase: structureactivity relationships. J Steroid Biochem
1978;9:10437.
[153] Petrow V, Wang Y-S, Lack L, Sandberg A. Prostatic cancer. I.6-Methylene-4-
pregnen-3-ones as irreversible inhibitors of rat prostatic
4
-3-ketosteroid
5-reductase. Steroids 1981;38:12140.
[154] Covey DF, Robinson CH. Conjugated allenic 3-oxo-5,10-
secosteroids.Irreversible inhibitors of
5
-3-ketosteroid isomerase. J
Am Chem Soc 1976;98:503840.
[155] Robaire B, Covey DF, Robinson CH, Ewing LL. Selective inhibition of rat
epididymal steroid
4
-5-reductase by conjugated allenic 3-oxo-5,10 sec-
osteroids. J Steroid Biochem 1977;8:30710.
[156] Cabeza M, Gutirrez E, Miranda R, Heuze I, Bratoeff E, Flores G, et al. Andro-
genic and anti-androgenic effects of progesterone derivatives with different
halogens as substituents at the C-6 position. Steroids 1999;64:41321.
[157] Cabeza M, Quiroz A, Bratoeff E, Murillo MaE, Ramirez E, Flores G. Synthe-
sis and pharmacological evaluation of 4-halo progesterone derivatives as
antiandrogen. Chem Pharm Bull 1999;47:12326.
[158] Ramirez E, Cabeza M, Heuze I, Gutierrez E, Bratoeff E, Membrillo M, et
al. Synthesis and pharmacological evaluation of new 16-methyl pregnane
derivatives. Chem Pharm Bull 2002;50(1):1520.
[159] Bratoeff EA, Herrera H, Ramirez E, Solorzano K, Murillo E, Quiroz A,
et al. Antiandrogenic effect of 16-substituted, non-substituted and D-
homopregnane derivatives. Chem Pharm Bull 2000;48(9):124955.
[160] Cabeza M, Heuze I, Bratoeff E, Murillo E, Ramirez E, Lira A. New progesterone
esters as 5-reductase inhibitors. Chem Pharm Bull 2001;49(9):10814.
[161] Flores E, Cabeza M, Quiroz A, Bratoeff E, Garcia G, Ramirez E. Effect of a
novel steroid (PM-9) on the inhibition of 5-reductase present in Penicillium
crustosum broths. Steroids 2003;68(3):2715.
[162] Cabeza M, Heuze I, Bratoeff E, Ramirez E, Martinez R. Evaluation of
new pregnane derivatives as 5-reductase inhibitors. Chem Pharm Bull
2001;49(5):52530.
[163] Cabeza M, Bratoeff E, Flores E, Ramrez E, Calleros J, Montes D, et al.
5-reductase inhibitory and antiandrogenic activities of novel steroids in
hamster seminal vesicles. Chem Pharm Bull 2002;50(11):144752.
[164] Bratoeff E, Ramrez E, Flores E, Valencia N, Snchez M, Heuze I, et al.
Molecular interactions of new pregnenedione derivatives. Chem Pharm Bull
2003;51(10):11326.
[165] Cabeza M, Flores E, Heuze I, Snchez M, Bratoeff E, Ramrez E, et al.
Novel 17 substituted pregnadiene derivatives as 5-reductase inhibitors
and their binding afnity for the androgen receptor. Chem Pharm Bull
2004;52(5):5359.
[166] Prez-Ornelas V, Cabeza M, Bratoeff E, Heuze I, Snchez M, Ramrez E,
et al. New 5-reductase inhibitors: in vitro and in vivo effects. Steroids
2005;70(3):21724.
[167] Cabeza M, Heuze I, Snchez M, Bratoeff E, Ramrez E, Rojas A, et al. Relative
binding afnity of novel steroids to androgen receptors in hamster prostate.
J Enzyme Inhib Med Chem 2005;20(4):35764.
[168] Ramrez E, Cabeza M, Bratoeff E, Heuze I, Prez V, Valdez D, et al. Synthesis
and pharmacological evaluation of new progesterone esters as 5-reductase
inhibitors. Chem Pharm Bull 2005;53(12):15158.
[169] Cabeza M, Bratoeff E, Heuze I, Rojas A, Teran N, Ochoa M, et al. New proges-
terone derivatives as inhibitors of 5-reductase enzyme and prostate cancer
cell growth. J Enzyme Inhib Med Chem 2006;21(4):3718.
[170] Bratoeff E, Sainz T, Cabeza M, Heuze I, Recillas S, Prez V, et al. Steroids with a
carbamate function at C-17, a novel class of inhibitors for human and hamster
steroid 5-reductase. J Steroid Biochem Mol Biol 2007;107(12):4856.
[171] Bratoeff E, Cabeza M, Prez-Ornelas V, Recillas S, Heuze I. In vivo and in
vitroeffect of novel 4,16-pregnadiene-6,20-dione derivatives as 5-reductase
inhibitors. J Steroid Biochem Mol Biol 2008;111(35):27581.
[172] Cabeza M, Zambrano A, Heuze I, Carrizales E, Palacios A, Segura T, et al. Novel
C-6 substituted and unsubstituted pregnane derivatives as 5-reductase
inhibitors and their effect on hamster ank organs diameter size. Steroids
2009;74(1011):793802.
[173] Occhiato EG, Guarna A, Danza G, Serio M. Selective non-steroidal inhibitors
of 5-reductase type 1. J Steroid Biochem Mol Biol 2004;88:116.
[174] Nakai H, Konno H, Kosuge S, Sakuyama S, Toda M, Arai Y, et al.New potent
antagonists of leukotrienes C4 and D4. 1. Synthesis and structureactivity
relationships. J Med Chem 1988;31:8491.
[175] Jones CD, Audia JE, Lawhorn DE, McQuaid LA, Neubauer BL, Pike AJ, et al.
Nonsteroidal inhibitors of human type I steroid 5-reductase. J Med Chem
1993;36:4213.
[176] Wikel JH, Bernis KG, Audia JE, Quaici LA, Jones CD, Pennington PA, et al.
QSARstudyof benzoquinolinones as inhibitors of humantype15-reductase.
Bioorg Med Chem Lett 1993;3:115762.
[177] Smith ECR, McQuaid LA, Goode RL, McNulty AM, Neubauer BL, Rocco
VP, et al. Synthesis and 5-reductase inhibitory activity of 8-substituted
benzo[f]quinolinones derived from palladium mediated coupling reactions.
[178] Abell AD, Prince MJ, McNulty AM, Neubauer BL. Simple bi and tri-
cyclic inhibitors of human steroid 5-reductase. Bioorg Med Chem Lett
2000;10:190911.
[179] Hartmann RW, Reichert M. New non-steroidal steroid 5alpha-reductase
inhibitors: syntheses and structureactivity studies on carboxam-
ide phenylalkyl-substituted pyridones and piperidones. Arch Pharm
2000;333:14553.
[180] Hartmann RW, Reichert M, Gring S. Novel 5 alpha reductase inhibitors: syn-
thesis and structureactivity studies of 5-substituted 1-methyl-2-pyridones
and 1-methyl-2-piperidones. Eur J Med Chem 1994;29:80717.
[181] Gring S, Reichert M, Hartmann RW. FC2 5-reductase inhibitors: synthesis
and structureactivity studies on newnon-steroidal compounds. Eur J Pharm
Sci 1994;2:1012.
[182] PicardF, Schulz T, HartmannRW. 5-Phenyl substituted1-methyl-2-pyridones
and 4
-substituted biphenyl-4-carboxylic acids. Synthesis and evaluation

as inhibitors of steroid 5-reductase type 1 and 2. Bioorg Med Chem
2002;10:43748.
[183] McCarthy AR, Hartmann RW, Abell AD. Evaluation of 4
-substituted bicyclic
pyridones as non-steroidal inhibitors of steroid 5-reductase. Bioorg Med
Chem Lett 2007;17:36037.
[184] Baston E, Palusczak A, Hartmann RW. 6-Substituted 1H-quinolin-2-ones and
2-methoxy-quinolines: synthesis and evaluation as inhibitors of steroid 5
reductases types 1 and 2. Eur J Med Chem 2000;35:93140.
[185] Picard F, Barassin S, Mokhtarian A, Hartmann RW. Synthesis and evalua-
tion of 2
-substituted 4-(4
-carboxy- or 4
-carboxymethylbenzylidene)-N-
acylpiperidines: highly potent and in vivo active steroid 5-reductase type
2 inhibitors. J Med Chem 2002;45:340617.
[186] Picard F, Baston E, Reichert W, Hartmann RW. Synthesis of N-substituted
piperidine-4-(benzylidene-4-carboxylic acids) and evaluation as inhibitors
of steroid 5-reductase type 1 and 2. Bioorg Med Chem 2000;8:147987.
[187] Streiber M, Picard F, Scherer C, Seidel SB, Hartmann RW. Methyl esters of N-
(dicyclohexyl) acetyl-piperidine-4-(benzylidene-4-carboxylic acids) as drugs
and prodrugs: a new strategy for dual inhibition of 5-reductase type 1 and
type 2. J Pharm Sci 2005;94:47380.
[188] Mook Jr RA, Lackey K, Bennett C. Synthesis of phenanthridin-3-one deriva-
tives: non-steroidal inhibitors of steroid 5-reductase. Tetrahedron Lett
1995;36:396972.
[189] Guarna A, Occhiato EG, Scarpi D, Tsai R, Danza G, Comerci A, et al. Synthesis of
benzo[c]quinolizin-3-ones: selective non-steroidal inhibitors of steroid 5-
reductase 1. Bioorg Med Chem Lett 1998;8:28716.
[190] Guarna A, Occhiato EG, Scarpi D, Zorn C, Danza G, Comerci A, et al. Synthesis
of 8-chloro-benzo[c]quinolizin-3-ones as potent and selective inhibitors of
human steroid 5-reductase 1. Bioorg Med Chem Lett 2000;10:3536.
[191] Guarna A, Machetti F, Occhiato EG, Scarpi D, Comerci A, Danza G, et al.
Benzo[c]quinolizin-3-ones: anovel class of potent andselectivenon-steroidal
inhibitors of human steroid 5-reductase 1. J Med Chem 2000;43:371835.
[192] Guarna A, Occhiato EG, Machetti F, Trabocchi A, Scarpi D, Danza G, et al. Effect
of C-ringmodications inbenzo[c]quinolizin-3-ones, newselectiveinhibitors
of human 5-reductase 1. Bioorg Med Chem 2001;9:138593.
[193] Occhiato EG, Ferrali A, Menchi G, Guarna A, Danza G, Comerci A, et al. Synthe-
sis, biological activity, and three-dimensional quantitative structureactivity
relationship model for a series of benzo[c]quinolizin-3-ones, nonsteroidal
inhibitors of human steroid 5-reductase 1. J Med Chem 2004;47:354660.
[194] Ferrali A, Menchi G, Occhiato EG, Danza G, Mancina R, Serio M, et al. Synthesis
and activity of 8-substituted benzo[c]quinolizin-3-ones as dual inhibitors of
human 5-reductases 1 and 2. Bioorg Med Chem Lett 2005;15:1458.
[195] Abell AD, Brandt M, Levy MA, Holt DA. A comparison of steroidal and non-
steroidal inhibitors of human steroid 5-reductase: new tricyclic aryl acid
inhibitors of the type-1 isozyme. Bioorg Med Chem Lett 1996;6:4814.
[196] Abell AD, Brandt M, Levy MA, Holt DA. A non-steroidal diene acid inhibitor of
humantype 2stereoid5-reductase. Bioorg MedChemLett 1994;4:232730.
[197] Baston E, Hartmann RW. N-substituted 4-(5-indolyl) benzoic acids. Synthesis
and evaluation of steroid 5-reductase type I and II inhibitory activity. Bioorg
Med Chem Lett 1999;9:16016.
[198] Reichert W, Jose J, Hartmann RW. 5-reductase in intact DU145 cells:
evidence for isozyme I and evaluation of novel inhibitors. Arch Pharm
2000;333:2014.
[199] Igarashi S, Inami H, Hara H, Fujii M, Koutoku H, Oritani H, et al. A novel
class of inhibitors for human steroid 5-reductase: synthesis and biological
evaluation of indole derivatives. II. ChemPharmBull (Tokyo) 2000;48:3828.
[200] Holt DA, Yamashita DS, Konialian-Beck AL, Luengo JI, Abell AD, Bergsma
DJ, et al. Benzophenone- and indolecarboxylic acids: potent type-2 specic
inhibitors of human steroid 5-reductase. J Med Chem 1995;38:135.
[201] Takami H, Koshimura H, Kishibayashi N, Ishii A, Nonaka H, Aoyama S, et al.
Indole derivatives as a new class of steroid 5-reductase inhibitors. J Med
Chem 1996;39:504752.
[202] Takami H, Kishibayashi N, Ishii A, Kumazawa T. Indole and benzimidazole
derivatives as steroid 5-reductase inhibitors in the rat prostate. Bioorg Med
Chem 1998;6:24418.
[203] Sawada K, Okada S, Kuroda A, Watanabe S, Sawada Y, Tanaka H. 4-
(Benzoylindolizinyl) butyric acids; novel non steroidal inhibitors of steroid
5-reductase. III. Chem Pharm Bull (Tokyo) 2001;49(7):799813.
[204] Picard F, Hartmann RW. N-Substituted 4-(4-carboxyphenoxy) benzamides.
Synthesis and evaluation as inhibitors of steroid-5-reductase type 1 and 2.
J Enzyme Inhib Med Chem 2002;17(3):18796.
[205] Baston E, SalemOIA, Hartmann RW. 6-Substituted 3,4-dihydro-naphthalene-
2-carboxylic acids: synthesis and structureactivity studies in a novel
class of human 5 reductase inhibitors. J Enzyme Inhib Med Chem
2002;17(5):30320.
[206] Salem OIA, Frotscher M, Scherer C, Neugebauer A, Biemel K, Streiber M, et
al. Novel 5-reductase inhibitors: synthesis, structureactivity studies, and
pharmacokinetic prole of phenoxybenzoylphenyl acetic acids. J Med Chem
2006;49:74859.
[207] Kato M, Komoda K, Namera A, Sakai Y, Okada S, Yamada, et al. Pyrrole
butyric acid derivatives as inhibitors of steroid 5-reductase. Chem Pharm
Bull (Tokyo) 1997;45:176776.
[208] Sawada K, Hirai H, Golden P, Okada S, Sawada Y, Hashimoto M, et al. (1-
Benzylindole-3-yl)alkanoic acids; novel nonsteroidal inhibitors of steroid5-
reductase(I). Chem Pharm Bull 1998;46(11):16837.
[209] Igarashi S, Kimura T, Naito R, Hara H, Fujii M, Koutoku H, et al. A novel class of
inhibitors for human steroid 5-reductase: phenoxybenzoic acid derivatives.
I. Chem Pharm Bull 1999;47(8):107380.
[210] Igarashi S, Inami H, Hara H, Koutoku H, Oritani H, Mase T. A novel class
of inhibitors for human and rat steroid 5-reductases: synthesis and bio-
logical evaluation of indoline and aniline derivatives. III. Chem Pharm Bull
2000;48(11):168997.
[211] Ishibashi K, Nakajima K, Sugioka Y, Sugiyama M, Hamada T, Horikoshi H, et
al. Synthesis and 5-reductase inhibitory activities of benzofuran derivatives
with a carbamoyl group. Bioorg Med Chem Lett 1998;8:5616.
[212] Ishibashi K, Nakajima K, Sugioka Y, Sugiyama M, Hamada T, Horikoshi H, et
al. Synthesis of 2-phenylbenzofuranderivatives as testosterone 5-reductase
inhibitor. Chem Pharm Bull 1999;47(2):22640.
[213] Nakai H, Terashima H, Arai Y. International Patent Application EP 0291245 A2
(November 17, 1988).
[214] Nakai H, Terashima H, Arai Y. Benzylaminophenoxybutanoic acid derivatives
as drugs for acne, alopecia, prostatic hypertrophy, their preparation, and for-
mulations containing them. Chem Abstr 110:708 (212384t).
[215] Blagg J, Ballard SA, Cooper K, Finn PW, Johnson PS, MacIntyre F, et al. The
development of non-steroidal dual inhibitors of both human 5-reductase
isozymes. Bioorg Med Chem Lett 1996;6:151722.
[216] Sawada K, Okada S, Golden P, Kayakiri N, Sawada Y, Hashimoto M, et al. 4-(1-
Benzoylindol-3-yl) butyric acids and FK-143: novel nonsteroidal inhibitors of
steroid 5-reductase (II). Chem Pharm Bull 1999;47(4):48191.
[217] Hirosumi J, Nakayama O, Fagan T, Sawada K, Chida N, Inami M, et al.
FK143, a novel, nonsteroidal inhibitor of steroid 5-reductase. 1. In vitro
effects on human and animal prostatic enzymes. J Steroid Biochem Mol Biol
1995;52:35763.
[218] Hirosumi J, Nakayama O, Chida N, Inami M, Fagan T, Sawada K, et al. FK143, a
novel nonsteroidal inhibitor of steroid 5-reductase. 2. In vivo effects on rat
and dog prostates. J Steroid Biochem Mol Biol 1995;52:36573.
[219] Baston E, Salem OIA, Hartmann RW. Cyclohex-1-ene carboxylic acids: syn-
thesis and biological evaluation of novel inhibitors of human 5-reductase.
Arch Pharm 2003;336:318.
[220] Fan G-J, Mar W, Park MK, Choi EW, KimK, KimS. Anovel class of inhibitors for
steroid 5-reductase: synthesis and evaluation of umbelliferone derivatives.
[221] Lesuisse D, Gourvest JF, Albert E, Doucet B, Hartmann C, Lefranc ois JM, et
al. Biphenyls as surrogates of the steroidal backbone. Part 2. Discovery of a
novel family of non-steroidal 5-reductase inhibitors. Bioorg Med ChemLett
2001;11:17136.
[222] Chen GS, Chang CS, Kan WM, Chang CL, Wang KC, Chern JW. Novel lead gen-
eration through hypothetical pharmacophore three-dimensional database
searching: discovery of isoavonoids as nonsteroidal inhibitors of rat 5-
reductase. J Med Chem 2001;44:375963.
[223] Hosoda S, Hashimoto Y. 3,3-Diphenylpentane skeleton as a steroid skeleton
substitute: novel inhibitors of human 5-reductase 1. Bioorg Med Chem Lett
2007;17:54148.
[224] Faragulla J, Bremmer J, Brown D, Grifth R, Heaton A. Comparative pharma-
cophore development for inhibitors of human and rat 5-reductase. J Mol
Graph Model 2003;22:8392.

An Overview On 5reductase Inhibitors

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Steroids 75 (2010) 109153

Contents lists available at ScienceDirect

-butyl the compound showed strong inhibitory activity

-alkyl chain with phenyl moiety gave

-yl)-4-methyl-4-aza-3-oxo-5-androst-1-ene-3-ones were syn-

) or isosteres of the carboxylate (NO

-substituted 5-aryl pyridones along with corresponding 1-aryl-

-N-substituted acetamide compounds (286289) while potent

-benzoyl substituent and also for compounds (291292) having

-acetamide (Table 32).

-carboxylic acids. In the dicyclohexylacetyl series,

-substituted biphenyl-4-carboxylic acids. Synthesis and evaluation

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