The hepatitis C virus (HCV) protease inhibitor telaprevir (VX-950, MP-
424,LY-570310) was approved by the U.S. FDA in May 2011 for the treatment
of genotype 1 chronic HCV infection in adult patients in combination with
peginterferon alfa and ribavirin (PR). Telaprevir and boceprevir (vide
supra) are the first two HCV protease inhibitors to be approved for
treatment of HCV infection. Telaprevir is a HCV NS3-4A protease
inhibitor that exerts its antiviral effect by blocking the release of
nonstructural viral proteins from a polyprotein precursor. Telaprevir is a
potent inhibitor of the protease (IC50=10 nM) and is active in cell culture
(HCV 1b replicon assay, EC50=354 nM). Telaprevir was identified from
efforts to truncate a decamer peptide inhibitor derived from the natural
substrate NS5A-5B and was guided by structure-based design. The ketoamide
group of telaprevir forms a covalent, reversible bond with the active
site serine hydroxyl of the protease and compensates for the loss of affinity
resulting from truncation of the peptide. Despite the presence of the reactive keto-amide group, telaprevir is >500-fold less potent against other serine
proteases. Synthesis of the key octahydrocyclopenta[c]pyrrole-1-carboxylic
acid fragment of telaprevir is achieved by a-deprotonation of Boc-protected
3-azabicyclo[3.3.0]nonane followed by reaction with CO2 and resolution of
the racemic acid. Alternatively, deprotonation is carried out in the
presence of a chiral amine to give the enantiomerically enriched acid.
