PRODRUGS

OBJECTIVES

1. Define prodrugs and understand the need for prodrugs

2. Understand how a drug candidate can be modified to generate a

prodrug

3. Identify how prodrugs approach can be used to overcome

certain issues with a drug candidate

4. Know some examples of currently used prodrugs

 INTRODUCTION
DEFINITION

The term prodrug refers to design of a pharmacologically inactive

compound that is converted to an active drug by metabolic
biotransformation

The biotransformation (activation) can occur prior, during, and after

absorption, or at specific target sites within the body.
NH2
O
O
H2N N H2N S NH2
N S NH2
O
O
prontosil sulfanilamide

Enzyme

CARRIER DRUG CARRIER + DRUG

Inactive Prodrug Nontoxic Active

APPLICATIONS

Prodrug design approach may be useful to overcome some of the

following problems

• solubility

• absorption and distribution

• site specificity

• instability

• prolonged release

• toxicity

• poor patient compliance

• formulation issues
 CLASSIFICATION OF PRODRUGS
1. Carrier-linked prodrugs
• contain a group that can be easily removed enzymatically (such as
an ester) to reveal the true drug
• ideally, the group removed is pharmacologically inactive and
nontoxic while the connecting bond must be labile for efficient
activation in vivo
Carrier-linked prodrugs can be further subdivided into:
• bipartate: composed of one carrier (group) attached to the drug
• tripartate: carrier group is attached via linker to drug
• mutual prodrugs: two drugs linked together

2. Bioprecursor prodrugs
• metabolized into a new compound that may itself be active or
further metabolized to an active metabolite (e.g. amine to
aldehyde to carboxylic acid)
 CARRIER-LINKED PRODRUGS
Types of Carrier Linkages
• What types of groups are the easiest to link to a carrier?
• What types of groups are the easiest to cleave from a carrier?
BIPARTATE PRODRUGS
1. Alcohol-Containing Drugs (Linked as Esters)
• Esters are readily synthesized
• Esters are easily hydrolyzed (esterases)
• Great range of hydrophobicity, hydrophilicity, and stabilities
available through the carrier group
• Alter the water solubility and consequently, absorption and
distribution
• Sulfates and phosphates are also included in this category and
can be cleaved by sulfatases and phosphatases, respectively.
O O O

DRUG OH + Cl R DRUG O R DRUG OH + HO R

 2. Carboxylic acid-Containing Drugs (Linked as Esters)
O O O

R OH + HO DRUG R O DRUG R OH + HO DRUG

3. Amine-Containing Drugs (Linked as Amides)

O O O

DRUG NH2 + Cl R DRUG HN R DRUG NH2 + HO R

• Simple amides are more stable than esters toward hydrolysis. However,
activated amides or amides of amino acids are more susceptible to
enzyme mediated cleavage.
• Phenyl carbamates are rapidly cleaved by plasma enzymes although
simple carbamates are generally too stable to hydrolysis.
O O

DRUG NH2 + Cl OR DRUG HN OR DRUG NH2 + HO R

carbamate prodrug + CO2

 3. Amine-Containing Drugs (Linked as Imines)

• Amines may be converted to imines (schiff bases)

- Schiff’s bases are more lipophilic (allowing access across
bloodbrain barrier) although labile to aqueous solutions
O O

DRUG NH2 + H R DRUG N R DRUG NH2 + H R

4. Carbonyl Compounds (Linked as Hydrolyzable Derivatives)

• The most common prodrugs of aldehydes and ketones are imines,
oximes, acetals (ketals), enol esters, oxazolidines and thiazolidines.

R R X
C O C
DRUG DRUG Y

O S
OR'
X C C C
C C NR' C NOH
Y OR HN N
H
 Examples of Carrier-linked Bipartate Prodrugs
1. Prodrugs for Increased Water Solubility
HO O OH

O
a. O O

O HO OH
HO OH
esterases H

H H
O
O
R

methylprednisolone R = H prednisolone (corticosteroid)

succinate ester R = CH3 methyl prednisolone

b. O O
H3 N+ O amidases H2N
N
O
R H O

amino acid amide of benzocaine Benzocaine (local anesthetic)

 Examples of Carrier-linked Bipartate Prodrugs

2. Prodrugs for improved Absorption and Distribution

a.
O NH OH
H
HO N
O esterase
O OH
HO
O

dipivefrin Epinephrine (anti-glaucoma)

 Examples of Carrier-linked Bipartate Prodrugs
3. Prodrugs for Site Specificity
HO
2-O
3PO
a. phosphatase

OH
OPO32-
Diethlystilbestrol
diethlystilbestrol diphosphate (breast cancer treatment)

O O O

DRUG O DRUG O oxidation DRUG O

BBB
b.
N N N+
CH3 CH3 CH3
O H H
N O
S
R
N HO hydrolysis
O DRUG +
O
O O N+
O CH3

N
CH3 -lactam antibiotic delivery to brain
 Examples of Carrier-linked Bipartate Prodrugs

4. Prodrugs for Stability (first-pass metabolism)

O NH
a.
O
O NH
glucuronidation OH
OH OH
O

HOOC
OH

propranolol (antihypertensive) propranolol O-glucuronide

O NH O
O O
O -O O
Drug OH
OH
DRUG O
+
O
propranolol hemisuccinate O

O
 Examples of Carrier-linked Bipartate Prodrugs

5. Prodrugs for Slow and Prolonged Release

O OH
a. N
N
O
F F
O O

Cl Cl
haloperidol (tranquilizer)
haloperidol decanoate (activity ~ 1 month i.m.)
(peak plasma ~ 2-6 hr oral)

b. S S

F F
N N
F F
F F

N N
O
N N
O OH
(CH2)5CH3

fluphenazine enanthate fluphenazine (antipsychotic)

(duration of activity ~ 1 month) (duration of activity 6-8 hrs)
 Examples of Carrier-linked Bipartate Prodrugs

6. Prodrugs to minimize toxicity

O
O OH
a. O
O O
NR1R2
O

ester derivative of aspirin aspirin (anti-inflammatory)

7. Prodrugs to encourage patient acceptance

Cl
O H
N
N
clindamycin (R = H)
O
H clindamycin phosphate (R = PO3H2)
HO S
clindamycin palmitate (R = CO(CH2)14CH3)
HO OR

clindamycin (antibacterial)
 TRIPARTATE PRODRUGS
• The carrier is not linked directly to the drug but instead through a linker

• Allows for decreased steric hindrance during enzymatic cleavage that

may occur with bipartate prodrugs

• Carrier is enzymatically cleaved from Linker

• Linker spontaneously cleaves from Drug

Enzyme

CARRIER Linker DRUG CARRIER + Linker DRUG

Nontoxic inactive
Inactive Prodrug

Linker + DRUG spontaneous

 TRIPARTATE PRODRUGS - Double Prodrugs

O O O O
esterases +
DRUG O O CARRIER DRUG O O- HO CARRIER

+
H2CO
DRUG OH

X = O, NH
DRUG X O CARRIER
 Examples of Carrier-linked Tripartate Prodrugs

a. O
H
HN S
NH2 N
O
OH
O
ampicillin (antibiotic)

O O
H H
HN S HN S
NH2 N NH2 N
O O
O O O
O
O O
O O O

bacampicillin pivampicillin
 MUTUAL PRODRUGS
• Useful when 2 synergistic drugs need to be administered at the same
site at the same time

• Mutual prodrug is bipartate or tripartate where a synergistic drug acts as

the carrier Cl
OH

NH

O Cl
Cl
normustard
OH
N O

Cl
estramustine (prostatic cancer treatment)

HO

estradiol
BIOPRECURSOR PRODRUGS
Bioprecursor prodrugs rely on oxidative or reductive activation reaction
unlike the hydrolytic activation of carrier-linked prodrugs
Metabolic Activation of Bioprecursor Prodrugs:
1. Oxidative Activation
• N- and O-Dealkylation
• Oxidative Deamination
• N-Oxidation
• Epoxidation
2. Reductive Activation
• Azo Reduction
• Sulfoxide Reduction
• Disulfide Reduction
• Bioreductive Alkylation
• Nitro Reduction
3. Nucleotide Activation
4. Phosphorylation Activation
5. Decarboxylation Activation
 BIOPRECURSOR PRODRUGS
N
1. Oxidative Activation N
N
a. N- Dealkylation
N N
NH2
N P450 Cl O
N N
N N
CH3 X
N X
Cl O CH3

X
X
alprazolam (x = H)
triazolam (x = Cl)
benzodiazepine (anxiolytic & sedative)

b. O- Dealkylation

C2H5
HN OH
HN O P450
O

acetaminophen
phenacetin
 BIOPRECURSOR PRODRUGS
1. Oxidative Activation
c. Oxidative deamination
H
O O
O O O
P O P Cl
Cl HO N H P O
N P450 N H 2N
Cl
N H
H N

Cl Cl
Cl
cyclophosphamide

OH
Cl O
P Cl
H3PO4 + NH3 HN H 2N O
N +
H

acrolein
Cl Cl (toxic)
nitrogen mustard
BIOPRECURSOR PRODRUGS
1. Oxidative Activation
d. N-Oxidation

H N N
N OH N+ OH
H
Cl-

5, 6 dihydropyridine pralidoxime
bioprecursor (acetylcholine esterase activator)

e. Epoxidation
O

N N

O NH2 O NH2

carbamazepine (anticonvulsant) carbamazepine 10, 11-oxide

 BIOPRECURSOR PRODRUGS
2. Reductive Activation
a. Azo reduction
NH2
O
O
H2N N H2N S NH2
N S NH2
O
O
prontosil sulfanilamide

b. Sulfoxide reduction
F F

O O

OH OH
S S
O

sulindac sulfide derivative

 BIOPRECURSOR PRODRUGS
2. Reductive Activation
c. Disulfide reduction
OH
Cl-

N N
N N+
S S OH
O S
N O N
NH2 NH2

thiamin tetrahydrofurfuryl disulfide thiamin

SH

3. Nucleotide Activation N
N
SH

N N
N
N
2-O PO
3 O

N
N H

6-mercaptopurine
HO OH

inhibits purine synthesis

 BIOPRECURSOR PRODRUGS

4. Phosphorylation Activation O
O
N
HN
N
HN
H2N N N
H2N N N
4-
O9P3O O
HO
O

OH
OH
ganciclovir substrate for DNA polymerase

5. Decarboxylation Activation

HO NH2 HO NH2

COOH + CO2
HO HO

levodopa dopamine
 SOFTDRUGS
• Biologically ACTIVE compounds that are rapidly metabolized by a
predictable route to pharmacologically non-toxic compounds
• Designed to undergo predictable metabolism via a built in labile group
• Short duration of action prevents possibility of toxicity and increases
therapeutic index
O
O

O N
HO N

N N
etomidate (hypnotic) Inactive metabolite

Cl-
O
COOH
O N+
O
O
+
HO +N(CH )
33

N+ COOH
Cl-

Succinylcholine (neuromuscular blocking agent)

 EXERCISE
1. Antibacterial Choramphenicol has low solubility. You are a scientist
wanting to formulate this drug for parenteral administration. Suggest some
approaches you may use to overcome the solubility problem
Hint : Hydroxyl group
OH Cl

H
N
Cl

O O
+
N HO

O-

2. Anti-inflammatory drug Tolmetin has a peak plasma concentration of about

1 hr. Suggest an approach to increase the duration of action of Tolmentin
O
Hint : Carboxylic acid

OH
N