Prodrugs

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Prodrugs
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• Sometimes drugs are designed to make use of
  metabolic processes in order to generate their
  active form.
• This is done in order to improve some selected
  property of the molecule, such as water
  solubility or ability to cross a membrane,
  temporarily.

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• Prodrugs currently constitute 5 of known drugs
  and a larger percentage of new drugs

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

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Active Form of Drug
Prodrug

• 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 candidate prodrug.

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• 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 COOHs, it was
  not orally bioavailable, and thus needed to be
  administered by injection.
• The monomethyl ester, enalapril (upper right) is
  orally bioavailable.

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• 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

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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.

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• Sometimes, in order to improve the esterase
  hydrolytic lability, an extension of the ester
  moiety is employed in order to remove steric
  encumbrances in the region of the ester carbonyl
  group (thus enabling it to fit the active site
  more readily).

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

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

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Required Reading

• Rautio, J. et. al Prodrugs design and clinical
  applications. Nature Reviews Drug Discovery
  2008, 7, 255-270.

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