| Literature DB >> 32551004 |
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.
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.Entities:
Year: 2020 PMID： 32551004 PMCID： PMC7294715 DOI： 10.1021/acsmedchemlett.0c00063
Source DB: PubMed Journal: ACS Med Chem Lett ISSN： 1948-5875 Impact factor: 4.345