Technocrats Institute of Technology-Pharmacy, Bhopal

Basic Concepts & Application of Prodrug Design

Medicinal Chemistry-III
Prepared by – Mrs. Sandra Gautam
Assistant Professor
Technocrats Institute of Technology – Pharmacy
Bhopal
 Technocrats Institute of Technology-Pharmacy, Bhopal
Basic concepts & Application of Prodrug design:

• INTRODUCTION:
 The potency, safety and financial investment of chemical entities are important
issues for development of new drug molecules.
 The therapeutic efficacy can be improved by overcoming the undesirable properties
while retaining the desirable ones.
 This can be achieved through biological, physical or chemical ways.
• Approaches of Prodrug design:
 The biological approach is to alter the route of administration which may or may
not be acceptable to patient.
 The physical approach is to modify the design of dosage form such as controlled drug
delivery of drug.
 The third and the best approach in enhancing drug selectivity while minimizing
toxicity, is the chemical approach for design of prodrugs.
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Definition & History of Prodrug design

• Definition:
 A prodrug is a chemically modified inert drug precursor, which upon biotransformation liberates the
pharmacologically active parent compound. Or
 A prodrug is a compound that is inactive or has low activity until it's converted into an active drug in
the body. Prodrugs are used to improve the drug's pharmacokinetics, or how it's absorbed,
distributed, metabolized, and excreted.

• History of Prodrugs:
 The term prodrug was first introduced by albert -1958 to describing, any compound that
undergoes biotransformation prior to exhibiting its pharmacological effects.
 Harper referred to this process as drug latentiatin that is chemical modification of a biologically
active compound to form a new compound that, upon in vivo enzymatic attack will liberate the parent
compound.
 The first compound fulfilling the classical criteria of a prodrug was acetanilide, introduced into the
medical practice by Cahn and Hepp in 1867 as an antipyretic agent.
 Acetanilide is hydroxylated to biologically active acetaminophen.
 Another historical prodrug is Aspirin (acetylsalicylic acid), synthesized in 1897 by Felix Hoffman
(Bayer, Germany), and Introduced in medicine by Dreser in 1899.
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Barrier related to physicochemical properties of drug:

1.Poor aqueous solubility – which being prevent the drug from administrated in the form
injectables.
2.Low lipophilicity- which limits the design lipid bond formulation.
3.Chemical instability- which prevent the drug to incorporate into adequate forms.

A)Barrier in the pharmacokinetic phase:

1.Incomplete absorption across biological membrane such as GIT mucosa & BBB.
2.Low & variable bioavailability due to extensive First pass effect.
3.Too rapid absorption or excretion when longer duration of the action is desired.
4.Lack of site specificity.

B)Barrier in the pharmacodynamic phase:

1. Toxicity.
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Objectives of Prodrug designing:

• There are three basic objectives in prodrug designing are-

A)Pharmaceutical objectives:
 To improve solubility, chemical stability, and organoleptic properties.
 To decrease irritation and/or pain after local administration.
 To reduce problems related with the pharmaceutical technology of the active agent.

B)Pharmacokinetic objectives:
 To improve absorption (oral and by non-oral routes).
 To decrease presystemic metabolism to improve time profile.
 To increase organ/ tissue-selective delivery of the active agent.

C)Pharmacodynamic objectives:
 To provide the desired pharmacological effects while minimizing adverse metabolic
and/or toxicological events.
 To improve the clinical and therapeutic effectiveness of those drugs which suffer from
some undesirable properties that otherwise hinder their clinical usefulness.
 To avoid the practice of clinically co administering two drugs in order to
enhance pharmacological activity or prevent clinical side effects.
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Properties of prodrug:

 Pharmacological Inertness.
 Rapid transformation, chemically or enzymatically, into the active form at the target site.
 Non-toxic metabolic fragments followed by their rapid elimination.
• Advantages & Disadvantages of Prodrug Design:
Advantages Disadvantages

It reduces adverse effects of drugs. Formulation of toxic metabolites.

Drug can be targeted to the desired The active doses of two mutual
sites. prodrugs of the same parent drugs
may appear to be same in rats but may
be quite different in clinical
investigations

Synergistic effects can be obtained The prodrug might consume a vital cell
without side effects constituent such as glutathione during
its activation stage which causes
depletion of prodrug.
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Classification of prodrugs:

A)Prodrug based on structural association of molecules

Carrier-linked prodrug
Bipartite prodrug
Tripartite prodrug
Mutual prodrug
Double prodrug
Bio precursor –
– Esters
– Prodrug for amide, imides and acidic compounds

B)Classification on basis of sites of conversion into active drug foam

Type 1
Type 2
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A)Carrier-linked prodrug:
 They are one where the active drug is covalently linked to an inert carrier.
 They are generally ester or amide.
 Such prodrugs have greatly modified lipophilicity due to the attached carrier.
 Carrier linked prodrug consists of the attachment of a carrier group to the active drug to alter its
physicochemical properties.
 The active drug is released by hydrolytic cleavage either chemically or enzymatically.
 E.g. Fosamprenavir: A prodrug that is activated to become amprenavir
– Enalapril, L-dopa, Prednisone
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•Bipartite prodrug:
 It is composed of one carrier (group) attached to the drugs.
 Such prodrugs have greatly modified lipophilicity due to the attached
carrier.
 The active drug is released by hydrolytic cleavage either chemically or
enzymatically.
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•Tripartite prodrug:
 The carrier group is attached via linker/spacer to drug.
 Eg:- Bacampicillin- Ampicillin prodrug.
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•Mutual prodrug:
 A mutual prodrug consists of two pharmacologically active agents coupled together so that each
acts as a promoiety for the other agent and vice versa.
 Where the carrier used is another biologically active drug instead of some inert molecule.
 The carrier selected may have the same biological action as that of the parent drug and thus
might give synergistic action, or the carrier may have some additional biological action that is
lacking in the parent drug, thus ensuring some additional benefit.
 Eg:- Benorylate is a prodrug of Paracetamol and Aspirin.
 Sultamicillin is a prodrug of Ampicillin and Salbactum.
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•Advantages
 Increased absorption.
 Injection site pain relief.
 Elimination of unpleasant taste.
 Decreased toxicity.
 Decreased metabolic inactivation.
 Increased chemical stability.
Double prodrug:
 where a prodrug is futher derivatized in a fashion such that only enzymatic conversion
to prodrug is possible before the latter can cleave to release the active drug.
 Eg:- Pilocarpic acid to pilocarpine.
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•Bioprecursor/Metabolic precursor:
 This prodrug does not contain carriers but ready up on metabolism to induce the
necessary functionally active species.
 Bioprecursor prodrugs rely on oxidative or reductive activation reactions unlike the
hydrolytic activation of carrier-linked prodrugs.
 They 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.
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•(B) Classification on basis of sites of conversion into active drug
foam

•Type I:
 Type I prodrugs are inactivated inside the cells (intracellulary).
 Eg:- Anti-viral nucleoside analogue.
 Acyclovir,fluorouracil, cyclophos phamide,diethylstilbestrol di phosphate,L-DOPA,
mercapto purine, mitomycin,zidovudine
•Type II:
 Type II prodrugs are bioactivated outside cells (extracellulary).
 Eg:- In digestive fluid or in the body’s circulation system.
 Loperamide oxide,oxyphenisatin, sulfasalazin.
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•Application of prodrugs:

•Pharmaceutical Applications

•Improvement of taste:
 One of the reasons for poor patient compliance, particularly in case of children, is the bitterness,
acidity or causticity of the drug.
 Two approaches can be utilized to overcome the bad taste of drug.
1.Reduction of the drug solubility in saliva.
2.To lower the affinity of drug towards taste receptor

•Thus making the bitterness or causticity imperceptible.

•Prodrug with improved taste

Parent Drug Prodrug with improved taste

Chloramphenicol Palmitate ester

Clindomycin Palmitate ester
Sulfoxazole Acetyl ester
Triamcinolone Diacetate ester
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2)Improvement of odour :
 The odor of the compound depends upon the pressure of vapour’s liquid with high vapour
pressure (& low B.P.) will have string odour.
 E.g. ethylmercapto is one such drug which is foul smelling liquid at B.P. 35c.

3)Change of physical form of drug:

 Some drugs which are in liquid form are unsuitable for formulation as a tablet especially if
their dose is high.
 The method of converting such liquid drug in solid prodrug involves formation of
symmetrical molecule having higher tendency to crystallize.
 Example: - ester of ethyl mercapto & trichloro –ethanol.
4) Reduction in GIT irritation
 Several drug cause irritation & damage to the gastric mucosa through directcontact
increased stimulation of acid secretion or through interference with protective mucosal
layer.
 The NSAID’s especially salicylates have such a tendency.
 They lower gastric PH & induce ulceration.
 Examples of prodrug design to overcome such problems of gastric distress are given
below.
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Parent Drug Prodrug that cause little/no gastric distress

1. Salicylic Acid Aspirin

2. Kanamycin Kanamycin Pamoate

5)Enhancement of chemical stability

 A drug may stabilize either during its self life or in the GIT when used orally.
 Self life stability is particularly important in case of the drug for I.V. use.
 The convential approach is to lyophilize such solution in to powder which can be
reconstituted before use.
 The prodrug design of such agent is also a good alternative to improve stability.
 An example of anti-neoplastic drug azacytidine.
 The aqueous solution of this drug is readily hydrolyzed but the bisulfate prodrug is
stable to such as degradation at acidic PH & is more water soluble than the parent
drug.
 The prodrug converts to the active drug at the physiological PH of 7.4.
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•Pharmacokinetic application
•1) Enhancement of bio-availability (lipophilicity):
 lipophilicity is an important prerequisite.
 A big advantage of increased bioavailability through increased lipophilicity is the
reduction in new dosage.
 For example: bacampicillin is as effective as ampicillin in just one-third of the dose
of latter.
• 2) Prevention of presystemic metabolism :
 Several corticosteroids undergo extensive first-pass hepatic metabolism which can be
prevent by use of their esters or either prodrugs.
 For example: triamcin Frequent dosing is required for drug having short biological
half-lives.
 This can be overcome by use of both controlled release &prodrug approaches.
 The two rate controlling steps in enhancement of duration of action of drug are:-
1. The rate of release of prodrug from the site of application or administration in to
the systemic circulation.
2. 2. The rate of conversion of prodrug in to active drug in the blood.
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2)Reduction of toxicity :
 An important objective of a drug design is to develop one which high active & low
toxicity.
 Example of drug for systemic use with local side effect such as gastric distress with
NSAID’s which can beovercome by prodrug design have already been discussed.
 Another example is bioprecursorsulindac.
 As a sulfoxide it does not cause any gastric distress & is absorbed better in
blood, it is converted.
3)Site-specific drug delivery:
 After its absorption in to the systemic circulation the drug is distributed to the various
part of body including target site as well as non-targeted tissue.
 A distribution pattern has various several.
 Disadvantages
a. The drug may lead undesirable toxic effect on non-targeting tissue.
b. A smaller fraction of the drug will reach its site because of dilution.
c. If target site has long distribution time, drug may be eliminated without reaching
such site.