Prodrugs
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Prodrugs
• 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
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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
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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
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Types of prodrugs
• 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
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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
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• Most common (biologically labile) functional groups utilized in
prodrug design are shown above.
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Prodrug Active Form of Drug
• Esters are the most commonly employed prodrugs.
• Numerous catalytic esterases are present in vivo to hydrolyze
simple esters.
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• 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
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Prodrugs
• 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
Diacetate ester of the corresponding diol
(penciclovir)
• Conversely, such a strategy can also be used to convert an
alcohol to a more lipophilic moiety, as shown above.
• 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.
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Prodrugs
• To minimize toxicity To Encourage Patient Acceptance
• To eliminate formulation problems Improved absorption Prodrugs
• Increased water solubility Bioprecursors
• Prontosil to sulfonamides Bioprecursors• Activation of leflunomide to active drug Bioprecursors• Sulfation activation Decarboxylation activation