Design of N-Benzoxaborole Benzofuran GSK8175 - Optimization of Human PK Inspired by Metabolites of a Failed Clinical HCV Inhibitor.

We previously described the discovery of GSK5852 (1), a non-nucleoside polymerase (NS5B) inhibitor of hepatitis C virus (HCV), in which a N-benzyl boronic acid was essential for potent antiviral activity. Unfortunately, facile benzylic oxidation resulted in a short plasma half-life (5 h) in human volunteers, and a backup program was initiated to remove metabolic liabilities associated with 1. Herein we describe second generation NS5B inhibitors including GSK8175 (49), a sulfonamide-N-benzoxaborole analog with low in vivo clearance across preclinical species and broad-spectrum activity against HCV replicons. An X-ray structure of NS5B protein co-crystallized with 49 revealed unique protein-inhibitor interactions mediated by an extensive network of ordered water molecules, and the first evidence of boronate complex formation within the binding pocket. In clinical studies, 49 displayed a 60-63 h half-life and a robust decrease in viral RNA levels in HCV infected patients, thereby validating our hypothesis that reducing benzylic oxidation would improve human PK and lower efficacious doses relative to 1.