Pro-drugs - Medicinal Chemistry III B. Pharma 6th Semester


       Initially used by Albert

       Is a pharmacologically inactive compound that is converted into an active drug by a metabolic biotransformation

       Can be enzymatic/non-enzymatic

       Non-enzymatic such as hydrolysis- compounds may cause stability problems  

       Conversion can occur before ADME or at specific site in the body

       Soft drug- pharmacologically active and uses metabolism for promotion of excretion

Why prodrug

Lead modification approach used to correct a flaw in drug candidate

       Aqueous solubility

       Absorption and distribution

       Site specificity


       Prolonged release


       Poor patient acceptability

       Formulation problems

Types of prodrugs

       A) Carrier linked prodrugs and B) Bioprecursors

       A) Carrier linked prodrugs- active drug linked to a carrier group

       Carrier group- should be labile, non-toxic, biologically inactive

       Further divided to bipartate, tripartate and mutual prodrugs

       Bipartate- prodrug with carrier

       Tripartate- carrier + linker + prodrug

       Mutual prodrug- synergistic drugs connected to each other 

       B) Bioprecursors- compound metabolized by molecular modification into new compound which can be drug

       No resemblance to desired functional group

       Drastic structural change is required to unmask desired group

       Oxidation is common metabolic biotransformation    

Carrier linked prodrugs

       An ideal drug carrier must

       (1) protect the drug until it is at the site of action;

       (2) localize the drug at the site of action;

       (3) allow for release of the drug chemically or enzymatically;

       (4) minimize host toxicity;

       (5) biodegradable, biochemically inert, and non-immunogenic;

       (6) be easily prepared inexpensively; and

       (7) be chemically and biochemically stable in its dosage form

       Most common (biologically labile) functional groups utilized in prodrug design are shown above.

                            Prodrug                                              Active Form of Drug

       Esters are the most commonly employed prodrugs.

       Numerous catalytic esterases are present in vivo to hydrolyze simple esters.

       However, different species have differing amounts and types of esterases with different substrate specificities and different rates of hydrolysis.

       This can make it difficult for pharmaceutical companies to generate accurate preclinical models in which to evaluate their candidate prodrug.

       One example is the monoethyl ester of enalaprilat, which is called enalapril.

       Enalaprilate (upper left) was first discovered as an inhibitor of angiotensin converting enzyme (ACE) and used to treat hypertension.

       Due to its high polarity, note two COOH’s, it was not orally bioavailable, and thus needed to be administered by injection.

       The monomethyl ester, enalapril (upper right) is orally bioavailable.

       Another example is the anti-viral agent Oseltamavir (Tamiflu®) shown above

       Notice that the oral bioavailability is improved by employing the ethyl ester of the carboxylic acid


       Such a strategy is employed for pivampicillin, as shown above.

       Such a strategy can also be used to (temporarily) convert phosphate groups into more lipophilic ester moieties, as shown above.

       Increased water solubility


       Activation of leflunomide to active drug


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