1378427-87-2Relevant academic research and scientific papers
Design of N-Benzoxaborole Benzofuran GSK8175 - Optimization of Human Pharmacokinetics Inspired by Metabolites of a Failed Clinical HCV Inhibitor
Chong, Pek Y.,Shotwell, J. Brad,Miller, John,Price, Daniel J.,Maynard, Andy,Voitenleitner, Christian,Mathis, Amanda,Williams, Shawn,Pouliot, Jeffrey J.,Creech, Katrina,Wang, Feng,Fang, Jing,Zhang, Huichang,Tai, Vincent W.-F.,Turner, Elizabeth,Kahler, Kirsten M.,Crosby, Renae,Peat, Andrew J.
supporting information, p. 3254 - 3267 (2019/03/19)
We previously described the discovery of GSK5852 (1), a non-nucleoside polymerase (NS5B) inhibitor of hepatitis C virus (HCV), in which an 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 cocrystallized 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 pharmacokinetics and lower efficacious doses relative to 1.
