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Seminar on

Presented By
M.PHARM -1ST YEAR Pharmaceutical chemistry

K.L.E Universitys College Of Pharmacy

Vidyanagar, Hubli -31

Introduction &Terminology Objectives Prodrug design Barriers and their overcoming Types of prodrugs Challenges in design Current research strategies References

The term prodrug was initially used by Albert in 1958. Definition: A prodrug is a pharmacologically inactive compound that is converted in to active drug by metabolic biotransformation.

Prodrug can also be called as Pro-agent, bioreversible derivative or latentiated drug.

Drug Latentiation:

the process of purposely designing and synthesizing a molecule that specifically requires bioactivation to a pharmacologically active substance.

Hard Drugs:
These are non-metabolizable compounds characterized either by high lipid solubility and accumulation or high water solubility.

Celecoxib (t 9h)

Hard drug (t 680h)

Soft Drugs:
Biologically active compounds characterized by apredictable and fast in-vivo metabolism to inactive and non-toxic moieties, after they have achieved their therapeutic role.
Ex: Lonteprednol etabonate

An endogenous prodrug is the proinsulin which is synthesised inpancreas and released as its active moiety insulin. Natural prodrug codeine & heroin.


To improve patient acceptance To improve formulation stability To prolong duration of action To improve site specificity To decrease side effects To reduce pain at the site of injection.


POST HOC DESIGN: Post hoc design is done for established drugs to improve its pharmaceutical property and / or targetting. Ex:- chloramphenicol palmitate from chloramphenicol. AD HOC DESIGN: Ad hoc design is done for lead candidates suffering from severe drawback in drug-like properties. Ex:- Aspirin from salicylic acid.

Rational prodrug design consists of three basic steps Identification of drug delivery problem. Identification of physicochemical properties required for maximum efficacy. Selection of transport moiety exhibiting proper physicochemical properties and can be cleaved in a desired biological compartment.

Barriers and over comings

Pharmaceutical barriers Pharmacokinetic barriers Pharmacodynamic barriers

A) Pharmaceutical barriers
To improve stability: The presence of free OH group in propranolol leads to rapid metabolism of it. So its hemisuccinate is used as prodrug.

To increase water solubility:

Chloramphenical succinate

To improve taste and odour:

Chloramphenicol palmitate

Boiling point = 35oc

Boiling point > 35oc

Reduction of pain at injection site:



R = HPO3 clindamycin phosphate

B. Pharmacokinetic barriers
Improved absorption and distribution:

Prevention of presystemic metabolism:

R= H, Propranolol R= COCH2CH2COO Propranolol hemisuccinate

Prolongation of duration of action:

R = H, Haloperidol R = CO(CH2)8CH3, Haloperidol decanoate

C. Pharmacodynamic barriers
To lower toxicity:

For site specificity:


Types of Prodrugs
According to Wermuth prodrugs are generally classified in to 1. Carrier linked prodrugs 2. Bioprecursors

Carrier linked prodrugs are further divided in to

a) Bipartate prodrugs b) Tripartate prodrugs

c) Mutual prodrugs
d) Macromolecular drug carriers e) Enzyme prodrug therapies

Carrier Linked Prodrugs

A drug carrier should Protect the drug until it is at the site of action. Localize the drug at site of action. Allow for release of drug chemically or enzymatically. Minimize host toxicity. Biodegradable, biochemically inert and immunogenic. Be easily prepared inexpensively. Be chemically and biochemically stable in its dosage form.


Why esters are the first choice? 1. Esters are ubiquitous. 2. Ester prodrugs with any degree of hydrophilicity or lipophilicity. 3. Degree of stability can be varied by manipulation of electronic and steric factors. Alchols + long chain carboxylic acid Alchols + carboxylic acids with amino acids solubility solubility

Succinate esters intramolecular catalysis

Enolic hydroxyl groups ester prodrugs


oxindole fumarate

Drugs containing primary amine group can undergo aminolysis reactions leading to toxic products. So prodrug approach is necessary for these drugs. Amine prodrugs are generally stable towards metabolism. But low basicity amines and their mannich base derivatives are liable for metabolism. Types of amine prodrugs: Mannich bases Schiff bases Reduction for activation

Mannich bases-amine prodrugs

Water solubility of rolitetracyclin can be increased by mannich base formation.


Partition coefficient can be increased by N-mannich base formation as seen in phenylpropanolamine and its prodrug.

R = H.HCl Phenylpropanolamine hydrochloride R = CH2 NHCOC6H5 N-mannich base derivative

Generally carbamates are stable, but phenyl carbamates are rapidly cleaved by plasma enzymes.

SCHIFF BASES (amine imine)

Lipophilicity of amines can be increased by converting them to Schiff bases. Ex: Anticonvulsant agent progabide is a prodrug of -amino butyric acid.

Reduction for activation

This technique was mainly used for treatment of cancer. Because tumors are normally hypoxic in condition.

Acetylation of sulfonamide generated acidic proton which makes them water soluble. Ex:- anti-inflammatory agent valdicoxib can be converted to parecoxib sodium.




It is a carrier-linked bipartate prodrug approach that has been utilized to improve site specificity, protection of drug from biodegradation and minimization of side effects. In this system drug is covalently attached to macromolecule such as synthetic polymer, glycoprotien, lipoprotien, hormone, liposome, albumin, an antibody or a cell.

Aspirin linked to polyvinyl alcohol showed same potency as that of aspirin but was less toxic.

Ibuprofen attached to polyoxyethylene diester resulted in a sustained release form.

No androgenic activity

significant androgenic activity

Amino acids as drug carriers

Synthetic carriers are replaced with natural biodegradable amino acid carriers. Ex:- antitumor drug Methotrexate is attached to poly (L-lysine). Advantages:1. Increased cellular uptake a new way to overcome drug resistance to deficient drug transport. 2. It is more specific to tumor cell lines than human lymphocytes.

According to Ringsdorf A drug is attached to polymer backbone usually through spacer so that it can be cleaved hydrolytically or enzymatically without steric hindrance.
Site specificity can be manipulated by attachment of homing device.

Site specific delivery

DNA synthesis inhibitors like floxuridine and cytosine arabinoside were conjugated with albumin. Because of high protien uptake by cancer cells, their concentration inside cell increases.




Carrier Link er Drug enzyme Carrier + Link er Drug

spon taneou s

Link er


O Drug XCH2 OCR esteras e Drug XCH2 Ofas t

Drug X




Reversible redox tripartate drug delivery

Ex:- -lactam antibiotics to treat bacterial meningitis.

A mutual prodrug is a bipartate or tripartate prodrug in which the carrier is a synergistic drug with the drug to which it is linked. Ex:- antibiotic + - lactamase inactivator.


Azo reductase


5-amino salicylic acid


Mainly there are two challenges in prodrug design. 1. Biological variability 2. Toxicity potential Biological variability: The high levels of carboxylesterases in the plasma of rodents but not of other mammals effect the rate and site of activation of ester prodrugs.

It can be overcomed by developing drugs activated by non-enzymatic hydrolysis.

A more promising approach to combat biological variability is that two-step activation of carrier linked prodrugs.

TOXICITY POTENTIAL: There are mainly 2 sources of toxicity. 1. Toxic metabolite formed from promoiety. 2. Reactive metabolic intermediate.

Ex:- Arylacetylenes were inetially examined as potential bioprecursors for NSAID drugs. But later highly reactive ketene as intermediate was noticed during its metabolism.

Current research
Lisdexamphetamine, psychostimulant was approved by FDA on 2007. It is a prodrug of amphetamine.


Moriarty LM reported new Aspirin prodrugs which have sustained platelet inhibition function up to 24 hours.

Isosorbide diaspirinate ester

Capecitabine, prodrug of 5-flurouracil is under phase-3 clinical trail.


Silverman RB. The organic chemistry of drug design and drug action. 2004:497-527. Abraham DJ. Burgers medicinal chemistry and drug discovery. 6th edn, 2:499-525. Hanch C. Comprehensive medicinal chemistry. 5:122-133. Kadam SS, Mahadik KR, Bothara KG. Principles of medicinal chemistry. 2009,18th edn, 2:408-415. Moriarty LM. Discovery of true aspirin prodrug. J Med Chem. 2008,51:7991-7999. Rubin RL. D-Amphetamine prodrug new clinical research. Medical practice update. 2007.

Martino MM, Martino R. Clinical Studies of Three Oral Prodrugs of 5-Fluorouracil (Capecitabine, UFT, S-1): A Review. The oncologist. Bhosle D. Mutual prodrug concept: fundamentals and applications. Indian J Pharmceu Sci. 2006, 68:286-294.