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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