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Prodrugs II Prepared By Professor Mohamed Ahmed Moustafa Professor Mohamed Ahmed Moustafa Professor of Medicinal Chemistry

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  • Prodrugs IIPrepared By Professor Mohamed Ahmed MoustafaProfessor of Medicinal Chemistry


  • Site-specific drug delivery attempts to obtain very precise and direct effects at the site of action without subjecting the rest of the body to significant levels of the active agent. Prodrugs for Site SpecificityThe targeting of drugs for a specific site in the body by conversion to a prodrug is plausible when the physicochemical properties of prodrug are optimal for the target site.It should be kept in mind, however, that when the lipophilicity of a drug is increased, it would improve passive transport of the drug nonspecifically to all tissues.

  • Prodrugs for (increased) Site SpecificityTo increase the site specificity of certain drugs, the following means of preparing prodrugs are used: Increase or reduction in volume Alteration of hydrophilicity or solubility Introduction or removal of cationic or anionic moieties Change of pKa Incorporation of hydrocarbon or other suitable stable or labile moieties, and carriers that transport the compound to specific organs or tissues and make it to accumulate selectively there, where it is bioactivated.

  • Prodrugs for GITA nice objective of using prodrugs is to restrict the drug action to the upper part of the GIT If we want to target drugs against an infection of the GIT, then we want to prevent the drugs being absorbed into the blood supply. How??Retardation of the drug absorption, as in case of sulfathiazole

  • How would you decrease the absorption of this drug?This can easily be done by using a fully ionized molecule which is incapable of crossing cell membranes.The incorporation of strongly hydrophilic moieties to the sulfonamides prevents their transport to the bloodstream.They are incapable of crossing the gut wall and are therefore directed efficiently against the GI infection.

  • Prodrugs for (increased) Site Specificityused as intestinal antibacterial agent.These prodrugs act almost exclusively inside the intestinal tract.The succinyl or phthalyl group is good enough to decrease lipophilicity of the compound.The hydrophilic group makes the molecule poorly absorbed, preventing its transportation to the circulation.

  • Prodrugs for (increased) Site SpecificityBitolterol, a prodrug of the -blocker colterol.The toluate groups in both aromatic hydroxyls prevent the methylation of one of the groups by the enzyme COMT, until these groups are removed by hydrolysis by the esterases present in the tissues and in the blood.Bitolterol accumulates selectively in the lungs, where it partially and immediately releases colterol, which stimulate -adrenergic receptors and then adenylatic cyclase, with the consequent relaxation of the bronchial smooth muscles.EsteraseBitolterolColterol

  • Blood-brain barrier (BBB) is one of important membrane often targeted for drug delivery. It is unique lipid-like protective barrier that prevents hydrophilic compounds from entering the brain unless they are actively transported.a The blood brain barrier contains active enzyme systems to protect the CNS even further.Consequently, molecular size and lipophilicity are often necessary, not sufficient, criteria for gaining entry into the brain.

  • Prodrugs for (increased) Site SpecificityBodor and co-workers have devised a reversible redox drug delivery system (RRDDS) for getting drugs into the CNS and then, once in, preventing their efflux.

    The approach is based on the attachment of a hydrophilic drug to a lipophilic carrier (a dihydropyridine) thereby making prodrug that actively transported into the brain.

  • Prodrugs for (increased) Site SpecificityOnce inside the brain, the lipophilic carrier is converted enzymatically to a highly hydrophilic species (positively charged), which is then enzymatically hydrolyzed back to the drug and N-methylnicotinic acid, which is eliminated from the brain.

    The oxidation of the dihydropyridine to the pyridinium ion (half-life generally 20-50 min) prevents the drug from escaping out of the brain because it becomes charged.This drives the equilibrium of the lipophilic precursor throughout all of the tissues of the body to favor the brain.

  • Prodrugs for (increased) Site Specificity

  • Prodrugs for (increased) Site SpecificityThe functional group on the drug should be an amino, hydroxyl, or carboxyl group.When it is a carboxylic acid, the linkage is an acyloxymethyl ester, which decomposes as in pivampicillin.

  • Prodrugs for (increased) Site SpecificityAny oxidation occurring outside of the brain produces a hydrophilic species that can be rapidly eliminated from the body.The released oxidized carrier is relatively nontoxic and easily eliminated from the brain.Although this is a carrier-linked prodrug, it requires enzymatic oxidation to target the drug to the brain.The oxidation reaction is a bioprecursor reaction.

  • Prodrugs for (increased) Site SpecificityThe brain delivery of -lactam antibiotics for the possible treatment of bacterial meningitis.Since the -lactam antibiotics are hydrophilic, they enter the brain very slowly, but they are actively transported back into the blood.Therefore, they are not as effective in the treatment of brain infections as elsewhere.Bodor and co-workers prepared a variety of penicillin prodrugs attached to the dihydropyridine carrier through various linkers and showed that -lactam antibiotics could be delivered in high concentrations into the brain.


  • Prodrugs for (increased) Site SpecificityIncreasing the brain concentration of the inhibitory neurotransmitter -aminobutyric acid (GABA) results in anticonvulsant activity.GABA is too polar to cross the blood-brain barrier, so it is not an effective anticonvulsant drug.To increase the lipophilicity of GABA, a series of GABT and -aminobutyric Schiff bases were synthesized.Progabide emerged as an effective lipophilic analog of GABA that crosses the blood-brain barrier, releases GABA inside the brain, and shows anticonvulsant activity.

  • Prodrugs for (increased) Site SpecificityThe synthesis of a glyceryl lipid (R=linolenoyl) containing one GABA molecule and one vigabatrin molecule, a mechanism-based inactivator of GABA aminotransferase and anticonvulsant drug.This compound inactivates GABA aminotransferase in vitro only if brain esterases are added to cleave the vigabatrin from the glyceryl lipid.It also is 300 times more potent than vigabatrin, in vivo, presumably because of its increased ability to enter the brain.

  • Prodrugs for (increased) Site Specificitythe application prodrugs to site-specific drug delivery -Glutamyl dopa is an example of a site-specific prodrug of levodopa (L-dopa).L-dopa is precursor of the neurotransmitter dopamine, which plays an important role in the CNS and also exerts receptor-mediated vasodilation in the kidney.

  • Prodrugs for (increased) Site SpecificityIntraperitoneal injection of -glutamyl dopa into mice led to the selective generation of dopamine in the kidney as a consequence of the sequential actions of -glutamyl transpeptidase and L-aromatic amino acid decarboxylase, two enzymes that are highly concentrated in the kidney.The concentration of dopamine in the kidney after -glutamyl dopa administration was five times higher than that after administration of an equivalent dose of L-dopa.

  • Prodrugs for (increased) Site SpecificityThis does occur in a very selective manner, suggesting that some N-acyl--glutamylsulfamethoxazole derivatives may be useful as specific renal antibacterial agents and -glutamyllevodopa or -glutamyldopamine as specific renal vasodilators.

  • Prodrugs for (increased) Site SpecificityDesign a prodrug that requires activation by an enzyme found predominantly at the desired site of action.For example, tumor cells contain a higher concentration of phosphatases and amidase than do normal cells.Consequently, a prodrug of a cytotoxic agent could be directed to tumor cells if either of these enzymes were important to the prodrug activation process.

  • Prodrugs for (increased) Site SpecificityDiethylstilbestrol diphosphate was originally designed for site-specific delivery of diethylstilbestrol to prostatic carcinoma tissue.In general, though, this tumor-selective approach has not been very successful because the appropriate prodrugs are too polar to reach the enzyme site, the relative enzymatic selectivity is insufficient, and the tumor cell perfusion rate is too poor.

  • designing prodrugs that are activated by enzymes found mainly at the target site.This strategy has been used to design antitumour drugs because tumors contain higher proportions of phosphatases and peptidases than normal tissues.For example, diethylstilboestrol diphosphate (Fosfestrol) has been used to deliver the oestrogen agonist diethylstilboestrol to prostatic carcinomas.

  • Prodrugs for (increased) Site SpecificityCertain glycosides of antiinflammatory steroids designed to release the parent drugs in the colon.Since drug glycosides are bulkier and generally more hydrophilic than the corresponding drugs, their ability to cross the biological membranes is reduced.Steroid glycosides are not cleaved by the enzymes of the small intestine.In the colon, however, they are hydrolyzed by the bacterial glycosidases, thus liberating the parent drugs in the large intestine.

  • Prodrugs for (increased) Site SpecificityTwo interesting examples are the prodrugs of N-acetylated sulfamethoxazole and of levodopa in which the carrier moieties are glutamic acid derivatives.These prodrugs were designed on basis of the finding of a particularly high concentration of an N-acylamino acid deacylase and -glutamyl transpeptidase in th

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