Aza follow-ups to BI 207524, a thumb pocket 1 HCV NS5B polymerase inhibitor. Part 1: Mitigating the genotoxic liability of an aniline metabolite

摘要: A series of heterocyclic aza-analogs BI 207524 (2), a potent HCV NS5B polymerase thumb pocket 1 inhibitor, was investigated with the goal to reduce liability associated release genotoxic aniline metabolite in vivo. Analog 4, containing 2-aminopyridine isostere that is negative Ames test identified, and found provide comparable GT1a/1b potency 2. Although cross-species PK profile, poor predicted human liver distribution analog 4 allometry principles projected high doses achieve strong antiviral response patients, this work has provided path forward toward design novel inhibitors improved safety profiles.