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Drug Design

Dr. Reem K. Arafa


Assistant Professor of Pharmaceutical Chemistry Faculty of Pharmacy - Cairo University

Soft drugs & Hard drugs


Soft drugs : drugs that are rapidly metabolized by hydrolysis or by other pathways other than oxidation as they contain labile group that is easily cleaved e.g. esters

Soft drug

Metabolism

inactive & safe metabolite

Hard drugs : drugs that resist metabolizing enzymes & excreted unchanged, these drugs remain in the body for long time .

Hard drug

Resist Metabolism

Toxic metabolite

Design a hard drug from soft drug


** Design a hard drug from soft drug The metabolite stability of the drug is enhanced by protecting any labile group in the molecule or by replacing it by more stable substituents. e.g. 1: Acetyl choline has acetate ester (very soft) so rapidly cleaved but carbamate ester or ketones, are more resistant than acetate ester (i.e. harder). ** Design a soft drug from hard drug e.g. 2: Cetyl pyridinium chloride : antifungal hard drug resists metabolism oxidized to give toxic metabolite. * Active soft drug easily metabolized by esterase enzyme to give inactive & safe metabolite easily excreted.

Cetyl pyridinium chloride


O N
+

CH2

CH2

CH2 (CH2)12- CH3

Isosteric replacement

CH2 O

(CH2)12 - CH3

Cl

Hard drug Metabolism Toxic metabolites

Soft drug Metabolism


O N
+

CH2OH +

- (CH2)12-CH3 HO C

N +

CH2O

NonToxic metabolites

Examples of converting soft drugs into hard drugs


e.g.1 : Estradiol not orally active due to rapid metabolism. but Ethinyl estradiol is active orally because ethinyl is a bulky group that resist metabolism.
OH OH C CH

HO

HO
O

Estradiol ( Sof t drug)

Ethinyl estradiol ( Hard drug)

progesterone

e.g.2 : Progesterone: its 6 - methyl group acts as metabolic blocker

e.g.3 : Tolbutamide t1/2 =6 hrs taken 3-4 times daily

metabolic H3C (active) oxidation HOOC (inactive)

If we use metabolic blocker (Cl instead of CH3) it will resist metabolism & make t1/2 = 20 hrs ( Taken once / day)

H 3C (Tolbutamide) Short acting

Cl

(Chloropropamide) Long acting

M etabolic blocker

e.g.4 : Catecholamines & Salbutamol COMT enzyme make methylation of OH groupof catecholamines result in methoxy derivative i.e. prompt metabolism

HO HO

COMT

MeO HO

Whereas, Salbutamol has longer duration of action due to its CH2OH gp.
r ock e l b c i a b ol t e M
HO HO OH H N Me Me C Me

salbutamol

Prodrug = Drug Latentiation


Prodrug: is inactive drug in vitro that is converted to active drug in vivo by metabolic pathways.

Types of Prodrugs 1- Carrier Linked prodrugs: utilize hydrolysis type of metabolic activation. 2- Bioprecursor prodrugs: utilize oxidative or reductive type of metabolic activation.

Prodrug = Drug Latentiation


Objectives of Prodrug Design: 1. To Absorption & distribution ( bioavailability) Ex.1 : Dipivaloyl ester of Epinepherine to corneal absorption:
O OH HO CH-CH
2

OH O CH-CH
2

- NH-CH

-NH-CH

HO Epinephrine O

O Dipivaloyl ester (Prodrug)

Poor penetration to cornea in vivo

Good ocular absorption

Dipivaloyl prodrug used for treatment of Glucoma, after its absorption, as corneal aqueous humor has significant esterase active epinephrine

Ex.2 : To oral bioavailability for PenicillinG which can not be orally administered due to its as the ionizable COO gp. lipid solubility so to lipid solubility we prepare the double esters e.g. Pivampicillin & Bacampicillin

O NH NH2 N O S CH3 CH3 COOH


CH3 CH3 COOCH-O-C-O-C2H5 CH3 O CH3 CH3 CH3

Bacampicillin

- CH2- O- C- C O

Pivampicillin

Ex.3 : Corticosteroids can be made more suitable for topical absorption by esterification or acetonidation. e.g. Fluocinolone acetonide & fluocinolone acetate are prodrugs for topical antiinflammatory use.

O C Me HO Me F O F

CH 2 OH CH 3 O O CH 3
HO

O C Me

CH 2 OH

OCOCH 3

OH

acetonide

Me F O F

2. To patient acceptability : The structure of the drug can be modified to avoid unpleasant odour or taste, but once administered, the active drug is released Ex. to mask the bitter taste of Chloramphenicol (highly soluble & bitter) by using Palmitate ester (insoluble prodrug) (Chloramphenicol palmitate) to mask bitter taste

OH

OH CHCl2
O

N OH

N O O2N OH
O

CHCl2

ester
(CH2)14CH3
O

O2N

Chloramphenicol ( Bitter taste )

Chloramphenicol Pamitate (without Bitter taste )

3. To Solve Formulation problems : e.g. Increase water solubility Ex.1 : Prodrug for diazepam * Diazepam itself is water insoluble not suitable for IV inj * The open chain prodrug (glycyl amino benzophenone derivative) is highly ionized & water soluble when injected peptidases cleave an amino acid spontaneous cyclization of the product active diazepam which go to CNS.
CH3 O N H N O O
invivo amidase

R NH2 HOOC

R NH2 Cl

CH3 O N O H2N

Cl

Open chain prodrug (Water soluble)

CH3 O N Cl N

in

vi

vo a liz

n tio

c cy

Diazepam

Ex.2 : Prodrug for Chloramphenicol To improve solubility of chloramphenicol for its parental use by using aqueous solution of chloramphenical succinate or phosphate as water soluble esters & salt

OH

H
N
O

CHCl2

O
CH2- O - C ester

O
CH2- O - P

O2N

OH
Salt

O -Na+

Chloramphenicol ( poor solubility )

Na+-O - C O Chloramphenicol Succinate

O -Na+
Chloramphenicol Phosphate ester + ionizable salt

Ex.3 : Prednisolone water soluble injectable form By formation of Phosphate ,Succinate Or Sulphate ester salt
R-gp.

O
CH2-OH O=C OH HO HO CH2-O-C-CH2-CH2-COO-Na+ O=C OH

Water soluble

Prednisone
Prednisone Sodium Succinate ester

O R = - C -CH2-CH2 -COO-Na+ O R = -P
O-Na+ O-Na+

Sodium Succinate

Disodium Phosphate

O R = - C -CH3 Acetate ester

4. To decrease Toxicity ( side effect ) : The drug is administered in a nontoxic, inactive form & then slowly converted to the active form. ** So by design of naproxen prodrug the gastric ulceration as side effect of NSAIDs can be avoided

CH2O-CO(CH2)11CH3 H3CO CH2-CH-COOH CH3 Naproxen (Anti-inflammatory) With Gastric irritation side effect Diglycerides ester of Glycerol COO CH CH2O-CO(CH2)11CH3

5. To Prolong Duration Of drug action ( Prolonged release) : A common strategy in the design of slow release products is to make a long chain aliphatic ester. Because these esters hydrolyze slowly. e.g. 1: Haloperidol decanoate: (R= -CO(CH2)8CH3) Is more suitable form for treatment of psychotic patients. As it is injected I.M. as oil solution its antipsychotic effect lasts for 1 month. e.g.2 : fluphenazine decanoate injection lasts for 1 month and is a good prodrug for fluphenazine .
OR N Cl F
Haloperidol : R = H O R= C (CH2)8-CH3 S N CF3 N CH2 CH2 OR

CH2 CH2 CH2 N

Fluphenazine: R = H

6. To avoid drug instability: rapid metabolism of drug before its arrival to the target site inactivation e.g. firstpass effect. e.g. Naltrexone : is used for treatment of opioid addiction It undergoes extensive 1st pass metabolism (i.e. metabolized before arrival of its target site ) To solve this effect its PRODRUGS of : anthranilate or acetyl salicylate is designed. They 45-& 28-fold respectively more effective than Naltrexone itself

N
1. Anthranilate : R=

H2N O C

HO
O AcO

RO

2. Acetyl Salicylate:

R=

C O

Naltrexone : (R = H)

7. For Site specificity = Prodrug for selective distribution :

{ DRUG TARGETING } i.e. targeting the drug for a specific site or organ in the body

Drug Targeting
Ex.1 : Oxyphenisatin : Oxyphenisatin can be taken only rectally. The acetylated form can be taken orally & activated only in the intestine.

O O H3 C O O CH 3 HO OH

O N H Prodrug for oxyphenisatin can be taken orally

Terminal ileum N H

Active oxyphenisatin " bowel sterilant"

Ex.2 : Diethyl stilbosterol Phosphate (Fosphosterol ) Its more selective in treatment of prostatic cancer than DES as the prostatic cancer tissue contains high conc. of Phosphatase enzyme, where DES phosphate is reactivated only at the site of action

OH O

P
OH

OH O

P
OH

Ex.3 : Progabide : It is a prodrug for amino butyric acid (GABA) GABA itself is too hydrophilic and can not cross BBB

- So prodrug is used to increase lipophilicity to allow it to cross BBB, once inside the brain it is hydrolyzed to GABA.
OH N F NH2
Schiff's base linkage

art active p

Cl

Progabide

Ex.4 : Brain-specific delivery system :


by Dihydropyridine pyridinium system - To penetrate Blood brain barrier (BBB): Only lipophilic & non ionizable drug can cross BBB.
- By attaching a reversible redox drug delivery system to the drug cross BBB & Once inside the brain the carrier is oxidized into a hydrophilic compound to be kept in the brain which is slowly hydrolyzed to the drug.
O
C X- Drug N N BBB

O
C X- Drug Metabolism (Oxidase) + N

O
C X- Drug Quaternary ionicf orm (locked in brain)

Me
PRODRUG with carrier system 1,4-dihydropyridine-3-carboxylic acid

Me

Me

Hyd rolysis

Lipophilic

COOH

Active drug

+ N

Me
Trigonelline ( nontoxic)

e.g. 1 : Brain delivery of GABA (-Amino butyric acid) It is ionic so not penetrate BBB by using BBBcarrier system as follow :

BBB

H3+N CH2-CH2-CH2-COOGABA N

C NH CH 2-CH 2-CH 2-COO-C 6 H11

In vivo Cleavage { esterase}

( can not penetrate BBB)

Me
BBB Carrier System (Lipophilic) GABA

e.g. 2 : Brain delivery of -lactam antibiotics : For treatment of bacterial meningitis. -lactams are hydrophilic can not cross BBB by themselves. Attaching the dihydropyridine carrier to -lactams make them able to cross BBB. Tri partate prodrug: (( Double ester with penicillins ))
R C O O H N CH 3 CH3 O N C O Linker O X Oxidation N CH 3 C Brain N C O Carrier S CH3 CH 3 O O X N CH 3
( Highly hydrophilic ) Locked in brain

Double ester ( Highly lipophilic ) pass BBB

Gene Directed Enzyme Prodrug Therapy (GDEPT)


GDEPT is a gene-based two-step treatment for cancer: 1. In the first step, the gene for the exogenous enzyme carboxypeptidase G2 (CPG2) is targeted to the tumour by the use of a selective vector, 2. This is followed by administration of a prodrug that is activated by the enzyme.

A large number of prodrugs including novel have been designed that are converted to a range of different classes of drugs. Thus the prodrug/drug system selected can be tailored for the tumour type.

(GDEPT)

(GDEPT)
CPG2 has been expressed in a variety of forms, both intracellular and tethered to the outer surface of mammalian cells. The former requires intracellular activation of prodrugs, whereas the latter allows this to be extracellular. Excellent cytotoxicity differentials are obtained between those cell lines that express the enzyme compared with the parent cell lines without the CPG2. Good cytotoxicity is obtained in vitro, when only 2% of the cells need to express the enzyme in order to achieve total cell ablation.

Bio-Precursor Prodrugs
Are inactive drugs in vitro and they are converted to its active form in vivo by chemical metabolic pathway.

Invivo Inactive Compound Metabolic reaction Active Compound

Bioprecursor prodrug utilize either oxidative or reductive type of metabolic activation. remember: carrier linked prodrugs are activated by hydrolysis

Metabolic activation of Bioprecursors


1) Oxidative activation :
N and O Dealkylations :

e.g. :

NHCOCH3
in-vivo
METABOLISM

NHCOCH3

OH OEt Phenacetin (inactive)

Acetaminophen (Paracetamol)
very active analgesic & antipyretic

Other Oxidations: e.g. :


in-vivo N O NH2 epoxidation O

N NH2

Carbamazepine

Carbamazepine 10-11 oxide (active)

2) Reductive activation: 1. Azoreduction: e.g. Prontosil is active in vivo H N only because it is metabolized to sulfanilamide by reduction of the azo group.
2

NH2 N N

O S O NH2

azoreductase H2N

O S O NH2

Prontosil

Sulfanilamide

2. Sulfoxide reduction: e.g.

CH2-COOH CH3

CH2-COOH CH3

in-vivo
Metabolic Reduction

O CH3 -S

CH3-S

Sulindac ( inactive )

Sulindac sulfide ( active )

3) Nucleotide Activation: 6-mercaptopurine is activated by a reaction with 5-phospho-ribosyl pyrophosphate catalyzed by hypoxanthine phosphoribosyl transferase. Only tumors that convert the drug to its nucleotide are effected
O O P O SH N N N N H O HO O O OH O O N O N O P O O O O SH O P O P O N N

phosphoribosyl pyrophosphate Hypoxanthine-guanine phosphoribosyl trans f erase

6-MP
inactive (prodrug) OH OH

6-Mercapto inosinate (active form)


Inhibit several enzymes in the purine nucleotide pathway

4) Decarboxylation activation: Parkinsonism is mainly due to a marked deficiency in the dopaminergic component. That is treated with high doses of DA. But DA cannot cross the BBB L-Dopa could be transported to the brain, where it will be decarboxylated DA
HO NH2
DOPA Decarboxylase

HO

NH2

COOH HO HO

L-Dopa
(Prodrug for dopamine)

Dopamine Rapidly degraded by MAO-B in brain So L-deprenyl is now used in combination with L-dopa