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.
Robert J Cherney  1 Lyndon A M Cornelius  1 Anurag Srivastava  1 Carolyn A Weigelt  1 David Marcoux  1 James J-W Duan  1 Qing Shi  1 Douglas G Batt  1 Qingjie Liu  1 Shiuhang Yip  1 Dauh-Rurng Wu  1 Max Ruzanov  1 John Sack  1 Javed Khan  1 Jinhong Wang  1 Melissa Yarde  1 Mary Ellen Cvijic  1 Arvind Mathur  1 Sha Li  1 David Shuster  1 Purnima Khandelwal  1 Virna Borowski  1 Jenny Xie  1 Mary Obermeier  1 Aberra Fura  1 Kevin Stefanski  1 Georgia Cornelius  1 Joseph A Tino  1 John E Macor  1 Luisa Salter-Cid  1 Rex Denton  1 Qihong Zhao  1 Percy H Carter  1 T G Murali Dhar  1
Affiliations
  • 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.

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