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) NS5B
replicase is a prime target for
the development of direct-acting antiviral drugs for the treatment
of chronic HCV infection. Inspired by the overlay of bound structures
of three structurally distinct NS5B palm site allosteric inhibitors,
the high-throughput screening hit anthranilic acid 4,
the known benzofuran analogue 5, and the benzothiadiazine
derivative 6, an optimization process utilizing the simple
benzofuran template 7 as a starting point for a fragment
growing approach was pursued. A delicate balance of molecular properties
achieved 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 efficiency
relative to early leads, demonstrated efficacy in a triple combination
regimen in HCV replicon cells, and exhibited consistently high oral
bioavailability and pharmacokinetic parameters across preclinical
animal species. The human PK properties from the Phase I clinical
studies of 37 were better than anticipated and suggest
promising potential for QD administration.