Discovery of BMS-986144, a Third-Generation, Pan-Genotype NS3/4A Protease Inhibitor for the Treatment of Hepatitis C Virus Infection
Li‐Qiang Sun, Eric Mull, Stanley V. D’Andrea, Barbara Zheng, Sheldon Hiebert, Eric P. Gillis, Michael Bowsher, Sarkunam Kandhasamy, Venkata Baratam, Sunitha Puttaswamy, Nagalakshmi Pulicharla, Sureshbabu Vishwakrishnan, S. Bharati Reddy, Ravi Trivedi, Sarmistha Halder Sinha, Sankar Sivaprasad, Abhijith Rao, Salil D. Desai, Kaushik Ghosh, Rushith Anumula, Amit Kumar, Ramkumar Rajamani, Ying-Kai Wang, Hua Fang, Arvind Mathur, Richard Rampulla, Tatyana Zvyaga, Kathy Mosure, Susan Jenkins, Paul Falk, Debarati M. Tagore, Chaoqun Chen, Kishore Rendunchintala, James Loy, Nicholas A. Meanwell, Fiona McPhee, Paul M. Scola
Abstract
The discovery of a pan-genotypic hepatitis C virus (HCV) NS3/4A protease inhibitor based on a P1–P3 macrocyclic tripeptide motif is described. The all-carbon tether linking the P1–P3 subsites of 21 is functionalized with alkyl substituents, which are shown to effectively modulate both potency and absorption, distribution, metabolism, and excretion (ADME) properties. The CF3Boc-group that caps the P3 amino moiety was discovered to be an essential contributor to metabolic stability, while positioning a methyl group at the C1 position of the P1′ cyclopropyl ring enhanced plasma trough values following oral administration to rats. The C7-fluoro, C6-CD3O substitution pattern of the P2* isoquinoline heterocycle of 21 was essential to securing the targeted potency, pharmacokinetic (PK), and toxicological profiles. The C6-CD3O redirected metabolism away from a problematic pathway, thereby circumventing the time-dependent cytochrome P (CYP) 450 inhibition observed with the C6-CH3O prototype.