Discovery of Novel Thiophene-Based, Thumb Pocket 2 Allosteric Inhibitors of the Hepatitis C NS5B Polymerase with Improved Potency and Physicochemical Profiles

The hepatitis C viral
proteins NS3/4A protease, NS5B polymerase,
and NS5A are clinically validated targets for direct-acting antiviral
therapies. The NS5B polymerase may be inhibited directly through the
action of nucleosides or nucleotide analogues or allosterically at
a number of well-defined sites. Herein we describe the further development
of a series of thiophene carboxylate allosteric inhibitors of NS5B
polymerase that act at the thumb pocket 2 site. Lomibuvir (1) is an allosteric HCV NS5B inhibitor that has demonstrated excellent
antiviral activity and potential clinical utility in combination with
other direct acting antiviral agents. Efforts to further explore and
develop this series led to compound 23, a compound with
comparable potency and improved physicochemical properties.