Design of N-Benzoxaborole Benzofuran GSK8175-Optimization of Human Pharmacokinetics Inspired by Metabolites of a Failed Clinical HCV Inhibitor.
Chong, P.Y., Shotwell, J.B., Miller, J., Price, D.J., Maynard, A., Voitenleitner, C., Mathis, A., Williams, S., Pouliot, J.J., Creech, K., Wang, F., Fang, J., Zhang, H., Tai, V.W., Turner, E., Kahler, K.M., Crosby, R., Peat, A.J.(2019) J Med Chem 62: 3254-3267
- PubMed: 30763090
- DOI: https://doi.org/10.1021/acs.jmedchem.8b01719
- Primary Citation of Related Structures:
6MVK, 6MVO, 6MVP, 6MVQ - PubMed Abstract:
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.
Organizational Affiliation:
GlaxoSmithKline , 5 Moore Drive , Research Triangle Park , North Carolina 27709 , United States.