Prodrugs In Medicinal Chemistry

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Prodrugs Introduction

An inactive precursor of a drug is converted into its active form in the body by normal metabolic processes. Prodrugs are used when drugs have unattractive physicochemical properties.

  • Prodrugs are reversible derivatives of drug molecules that undergo an enzymatic and/or chemical transformation in vivo to release the active parent drug, which can then exert the desired pharmacological effect.
  • In both drug discovery and development, prodrugs have become an established tool for
    improving the physicochemical, biopharmaceutical, or pharmacokinetic properties of pharmacologically active agents. ,
  • About 5-7% of drugs approved worldwide can be classified as prodrugs, and the implementation of a prodrug approach in the early stages of drug discovery is a growing trend.
  • The applicability of the prodrug strategy, this article describes the most common functional groups that are amenable to prodrug design and highlights examples of prodrugs that are either launched or are undergoing human trials.

Prodrugs Undesirable Properties

Physical Properties Poor

  • aqueous solubility Low
  • lipophilicity Chemical
  • instability Pharmacokinetic
  • Properties
  • Poor distribution across biological membranes
  • Good substrate for first-pass metabolism
  • Rapid absorption or excretion when long-term effect desired
  • Not site-specific

Prodrugs Can Be Classified Into Two Major Types, Based On How The Body Converts The Prodrug Into The Final Active Drug Form.

Type I prodrugs are bioactivated intracellularly: Examples of these are antiviral nucleoside analogs and lipid-lowering statins.

Type II prodrugs are bioactivated extracellular: Especially in digestive fluids or in the body’s circulation system, Examples of these are antibody, gene, or virus-directed enzyme prodrugs [ADEP/GDEP/ VDEP] used in chemotherapy or immunotherapy.

Some examples of Prodrug :

Carisoprodol is metabolized into meprobamate. Carisoprodol was not a controlled substance in the United States.

  • However, meprobamate was classified as a potentially addictive controlled substance that can produce dangerous and painful withdrawal symptoms upon discontinuation of the drug.
  • Enalapril is bioactivated by esterase to the active enalaprilat.
  • Valaciclovir is bioactivated by esterase to the active aciclovir.
  • Fosamprenavir is hydrolysed to the active amprenavir.
  • Levodopa is bioactivated by DOPA decarboxylase to activate dopamine.
  • Chloramphenicol succinate ester is used as an intravenous prodrug of chloramphenicol because pure chloramphenicol does not dissolve in water.
  • Psilocybin is dephosphorylated to the active psilocin.
  • Heroin is deacetylated by esterase to the active morphine.
  • Molsidomine is metabolized into SIN-1 which decomposes into the active compound nitric oxide.
  • Paliperidone is an atypical antipsychotic for schizophrenia. It is the active metabolite of risperidone.
  • Prednisone, a synthetic corticosteroid drug, is bioactivated by the liver into the active drug prednisolone, which is also a steroid.
  • Primidone is metabolized by cytochrome 450 enzymes into phenobarbital, which is major, and phenylethylmalonamide, which is minor.
  • Dipivefrine, given topically as an anti-glaucoma drug, is bioactivated to epinephrine.
  • Lisdexamfetamine is metabolized in the small intestine to produce dextroamphetamine at a controlled (slow) rate for the treatment of attention-deficit hyperactivity disorder
  • Diethylpropion is a diet pill that does not become active as a monoamine releaser or reuptake inhibitor until it has been Ndealkylated to ethylpropion.
  • Fesoterodine is an antimuscarinic that is bioactivated to 5 hydroxymethyl tolterodine, the principal active metabolite of tolterodine.
  • Tenofovir disoproxil fumarate is an anti-HIV drug (NtRTI class) that is bioactivated to tenofovir (PMPA).

Steps In Prodrug Design

Identification of drug delivery problem

  • Identification of desired physic-chemical properties
  • Selection of transport moiety which will give prodrug desired transport properties to be readily cleaved in the desired biological compartment

Depending upon the Nature of the Carrier used, the Carrier Linked prodrug Further Be Classified Into

Double prodrugs: pro-prodrugs, or cascade-latentiated prodrugs, where a prodrug is further derivatized in a fashion such that only enzymatic conversion to prodrug is possible before the latter can cleave to release the active drug.

1. Macromolecular prodrugs: where macromolecules like polysaccharides, dextrans, cyclodextrins, proteins, peptides, and polymers are used as carriers.

2. Site-specific prodrugs: where a carrier acts as a transporter of the active drug to a specific targeted site.

3. Mutual prodrug:

    • Where the carrier used is another biologically active drug instead of some inert molecule A mutual prodrug consists of two pharmacologically active agents coupled together so that each acts as a moiety for the other agent and vice versa.
    • 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.
    • The carrier may also be a drug that might help to target the parent drug to a specific site or organ or cells or may improve the site specificity of a drug. The carrier drug may be used to overcome some side effects of the parent drugs as well.

Criteria For Prodrug

A well-designed carrier-linked prodrug should satisfy certain criteria. The linkage between the drug and the carrier should usually be a covalent bond.

  • As a rule, the prodrug itself should be inactive or less active than the parent drug.
  • The linkage should be reversible. The prodrug and the earner released after an in vivo enzymatic or non-enzymatic attack should be nontoxic.
  • The generation of active form must take place ‘with rapid kinetics to ensure effective drug levels at the site of action.
  • The bioavailability of cancer-linked prodrug is modulated by using a transient moiety.
  • The lipophilicity is generally the subject of profound alteration of the parent molecule.
  • The bioactivation process is exclusively hydrolytic and sometimes a redox system. An ideal carrier should be without intrinsic toxicity.
  • It should be nonimmunogenic and non-antigenic and should not accumulate in the body.
  • It should possess a suitable number of functional groups for drag attachment and adequate loading capacity.
  • It should be stable to chemical manipulation and autoclaving.
  • It should be easy to characterize and should mask tire liganded drag’s activity until the release of active agent at the tire’s desired site of action.
  • In the mutual prodrug approach, the carrier should have some biological activity of its own.

Applications Of Prodrug

Prodrug to Improve Patient Acceptability:

  • One of the reasons for poor patient compliance, particularly in the case of children is the bitterness, acidity, or causticity of the drag. Two approaches can be utilized to overcome the bad taste of drag. The first is the reduction of drag solubility in saliva and the other is to lower the affinity of drag towards taste receptors.
  • Chloramphenicol has a bitter taste, so it is not well accepted by children. The pa Imitate ester of it is less soluble in saliva, so it masks the bitter taste.
  • Several drags (NSAIDS, Nicotinic acid, Kanamycin, Diethylstilboestrol) cause irritation and damage to the gastric mucosa.
  • Examples of prodrugs designed to overcome such problems of gastric distress are below (Aspirin & INH).

Prodrug to Improve Stability:

  • Many drugs are unstable and may either break down on prolonged storage or are degraded rapidly on administration.
  • Several drugs may decompose in GIT when used orally. Although enteric coatings may be used, it is also possible to utilize prodrug design to overcome this problem.
  • An anti-neoplastic drug Azacytidine hydrolyses readily in acidic pH, but the bisulfite prodrug is more stable.

Prodrug to improve absorption: Ampicillin a wide-spectrum antibiotic is readily absorbed orally as the inactive prodrug, Pivampicillin, Bacampicillin, and Talampicillin which are then converted by enzymatic hydrolysis to Ampicillin.

A prodrug for slow release (sustained drug action):

  • A common strategy in the design of slow-release prodrugs is to make long-chain aliphatic esters because these esters hydrolyze slowly and inject intramuscularly.
  • Fluphenazine has a shorter duration of action (68h), but the prodrug Fluphenazine deconate has a duration of activity of about a month.
  1. Prodrug to Improve Membrane Transport: Dopamine used for the treatment of Parkinson’s disease can be improved by administering its prodrug 3,4-dihydroxy phenylalanine (Levodopa).
  2. Prodrug for Prolonged Duration of Action: Nordazepam, a sedative drug loses activity quickly due to metabolism and excretion. A prodrug Diazepam improves the retention characteristics, due to the presence of N- methyl group.

Prodrugs Short Question And Answers

Question .1 What are the mutual prodrugs?
Answer:

The mutual prodrugs: Where the carrier used is another biologically active drug instead of some inert molecule a mutual prodrug consists of two pharmacologically active agents coupled together so that each acts as a moiety for the other agent and vice versa.

Question . 2 Write the steps of designing of prodrug.
Answer:

The steps of designing of prodrug

  • Identification of drug delivery problem
  • Identification of desired physic-chemical properties
  • Selection of transport moiety which will give prodrug desired transport properties to be readily cleaved in the desired biological compartment.

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