Discovery of a Hepatitis C Virus NS5B Replicase Palm Site Allosteric Inhibitor (BMS-929075) Advanced to Phase 1 Clinical Studies

The hepatitis C virus (HCV) NS5Breplicase is a prime target for the development of direct-acting antiviral drugsfor the treatment of chronic HCV infection. Inspired by the overlay of bound structures of three structurally distinct NS5Bpalm site allosteric inhibitors, the high-throughput screeninghit anthranilic acid4, the known benzofurananalogue 5, and the benzothiadiazinederivative 6, an optimization process utilizing the simple benzofurantemplate 7 as a starting point for a fragment growing approach was pursued. A delicate balance of molecular propertiesachieved via disciplined lipophilicity changes was essential to achieve both high affinity binding and a stringent targeted absorption, distribution, metabolism, and excretion profile. These efforts led to the discovery of BMS-929075 (37), which maintained ligand efficiencyrelative to early leads, demonstrated efficacy in a triple combination regimen in HCV repliconcells, and exhibited consistently high oral bioavailability and pharmacokineti...