Discovery of BMS-986251: A Clinically Viable, Potent, and Selective RORγt Inverse Agonist

Robert J Cherney; Lyndon A M Cornelius; Anurag Srivastava; Carolyn A Weigelt; David Marcoux; James J-W Duan; Qing Shi; Douglas G Batt; Qingjie Liu; Shiuhang Yip; Dauh-Rurng Wu; Max Ruzanov; John Sack; Javed Khan; Jinhong Wang; Melissa Yarde; Mary Ellen Cvijic; Arvind Mathur; Sha Li; David Shuster; Purnima Khandelwal; Virna Borowski; Jenny Xie; Mary Obermeier; Aberra Fura; Kevin Stefanski; Georgia Cornelius; Joseph A Tino; John E Macor; Luisa Salter-Cid; Rex Denton; Qihong Zhao; Percy H Carter; T G Murali Dhar

doi:10.1021/acsmedchemlett.0c00063

Discovery of BMS-986251: A Clinically Viable, Potent, and Selective RORγt Inverse Agonist

ACS Med Chem Lett. 2020 Mar 31;11(6):1221-1227. doi: 10.1021/acsmedchemlett.0c00063. eCollection 2020 Jun 11.

Authors

Robert J Cherney¹, Lyndon A M Cornelius¹, Anurag Srivastava¹, Carolyn A Weigelt¹, David Marcoux¹, James J-W Duan¹, Qing Shi¹, Douglas G Batt¹, Qingjie Liu¹, Shiuhang Yip¹, Dauh-Rurng Wu¹, Max Ruzanov¹, John Sack¹, Javed Khan¹, Jinhong Wang¹, Melissa Yarde¹, Mary Ellen Cvijic¹, Arvind Mathur¹, Sha Li¹, David Shuster¹, Purnima Khandelwal¹, Virna Borowski¹, Jenny Xie¹, Mary Obermeier¹, Aberra Fura¹, Kevin Stefanski¹, Georgia Cornelius¹, Joseph A Tino¹, John E Macor¹, Luisa Salter-Cid¹, Rex Denton¹, Qihong Zhao¹, Percy H Carter¹, T G Murali Dhar¹

Affiliation

¹ Bristol Myers Squibb Company, Research and Early Development, Princeton, New Jersey 08540-4000, United States.

Abstract

Novel tricyclic analogues were designed, synthesized, and evaluated as RORγt inverse agonists. Several of these compounds were potent in an IL-17 human whole blood assay and exhibited excellent oral bioavailability in mouse pharmacokinetic studies. This led to the identification of compound 5, which displayed dose-dependent inhibition of IL-17F production in a mouse IL-2/IL-23 stimulated pharmacodynamic model. In addition, compound 5 was studied in mouse acanthosis and imiquimod-induced models of skin inflammation, where it demonstrated robust efficacy comparable to a positive control. As a result of this excellent overall profile, compound 5 (BMS-986251) was selected as a clinically viable developmental candidate.