A high-throughput screening campaign aimed at identifying inhibitors of HCV with novel mechanisms-of-action identified a series of imidazopyridine analogs that exhibit potent antiviral activity.  Biochemical and genetic evidence suggest the compounds interact directly with NS4B, a viral protein critical for replication and for which few inhibitors have been described.  Optimization of the antiviral potency led to GSK337A, a potent inhibitor of both HCV GT1a and 1b replicons (EC50's of 0.6 and 0.3 nM, respectively).  The highly functionalized pyrazolopyridine core and the [3.1.0]-bicyclohexane sidechain with four contiguous chiral centers presented a number of synthetic challenges that were ultimately overcome thereby enabling the preparation of >100 grams of GSK337A.

Discovery and optimization of potent Hepatitis C antiviral agents that target NS4B

243rd National Meeting (2012)

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