2. Academic Validation
  3. Design of N-Benzoxaborole Benzofuran GSK8175-Optimization of Human Pharmacokinetics Inspired by Metabolites of a Failed Clinical HCV Inhibitor

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

  • J Med Chem. 2019 Apr 11;62(7):3254-3267. doi: 10.1021/acs.jmedchem.8b01719.
Pek Y Chong 1,  J Brad Shotwell 1,  John Miller 1,  Daniel J Price 2,  Andy Maynard 1,  Christian Voitenleitner 1,  Amanda Mathis 1,  Shawn Williams 3,  Jeffrey J Pouliot 3,  Katrina Creech 3,  Feng Wang 3,  Jing Fang 3,  Huichang Zhang 3,  Vincent W-F Tai 1,  Elizabeth Turner 1,  Kirsten M Kahler 1,  Renae Crosby 1,  Andrew J Peat 3
Affiliations

Affiliations

  • 1 GlaxoSmithKline , 5 Moore Drive , Research Triangle Park , North Carolina 27709 , United States.
  • 2 GlaxoSmithKline , 200 Cambridge Park Drive , Cambridge , Massachusetts 02140 , United States.
  • 3 GlaxoSmithKline , 1250 South Collegeville Road , Collegeville , Pennsylvania 19426 , United States.
PMID: 30763090 DOI: 10.1021/acs.jmedchem.8b01719
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.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-112047
    NS5B抑制剂
    HCV
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