Novel inhibitors of hepatitis C NS3–NS4A serine protease derived from 2-aza-bicyclo[2.2.1]heptane-3-carboxylic acid

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Abstract

Prolonged hepatitis C infection is the leading cause for cirrhosis of the liver and hepatocellular carcinoma. The etiological agent HCV virus codes a single polyprotein of ∼3000 amino acids that is processed with the help of a serine protease NS3A to produce structural and non-structural proteins required for viral replication. Inhibition of NS3 protease can potentially be used to develop drugs for treatment of HCV infections. Herein, we report the development of a series of novel NS3 serine protease inhibitors derived from 2-aza-bicyclo[2.2.1]-heptane carboxylic acid with potential therapeutic use for treatment of HCV infections.

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    The major isomer exo-1 could be reduced to give alcohol 2, which could be further used for the synthesis of various 2-azanorbornane8–10 and bridged azepane derivatives,11 which are useful as chiral building blocks, ligands and catalysts in asymmetric synthesis. 2-Azanorbornane derivatives have been recognized as valuable rigid analogues of various piperidine and pyrrolidine alkaloids, while 2-azabicyclo[2.2.1]heptane-3-carboxylic acid has been used as a proline mimic in an approach to develop constrained oligopeptides of possible therapeutic utility.1,12–14 The bicyclic chiral 2-azanorbornane or 2-azanorbornene system has also been found useful in the enantioselective preparation of cyclopentanoids.

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