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

Pro-drugs

•       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

•       Instability

•       Prolonged release

•       Toxicity

•       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

Famciclovir

•       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

Bioprecursors

•       Activation of leflunomide to active drug