Chuan-kui Jiang

TL;DR: The crystal structure of an analogue was solved and provided rationalization of the SAR of this series of non-nucleoside inhibitors targeting the HCV polymerase, which binds in a distinct manner in the palm domain of NS5B consistent with biochemical analysis using enzyme mutant variants.

TL;DR: Pyridine carboxamide-based inhibitors of the hepatitis C virus NS5B polymerase were diversified and optimized to a variety of topologically related scaffolds and identified this novel series of compounds as palm site binders to HCV polymerase.

TL;DR: Development of SAR at the C2 position of indole lead 1, a palm site inhibitor of HCV NS5B polymerase, results in identification of acyl sufonamide analog 7q with >100-fold improved replicon activity.

TL;DR: These efforts towards the identification and structure-activity relationship (SAR) of novel tricyclic indole derivatives that bind close to the palm site of the NS5B polymerase are described.

TL;DR: This manuscript describes further optimization of potency and pharmacokinetics of these inhibitors to identify compounds in low nM potency against gt-1b and demonstrates excellent PK in rats and monkeys when administered as a dimethyl ethyl amino ester prodrug.