2. Academic Validation
  3. Discovery of BMS-986251: A Clinically Viable, Potent, and Selective RORγt Inverse Agonist

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

Affiliation

  • 1 Bristol Myers Squibb Company, Research and Early Development, Princeton, New Jersey 08540-4000, United States.
PMID: 32551004 DOI: 10.1021/acsmedchemlett.0c00063
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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