BMS-986251的发现：一种具有临床可行性、强效且选择性的RORγt反向激动剂。
Discovery of BMS-986251: A Clinically Viable, Potent, and Selective RORγt Inverse Agonist.
作者信息
Cherney Robert J, Cornelius Lyndon A M, Srivastava Anurag, Weigelt Carolyn A, Marcoux David, Duan James J-W, Shi Qing, Batt Douglas G, Liu Qingjie, Yip Shiuhang, Wu Dauh-Rurng, Ruzanov Max, Sack John, Khan Javed, Wang Jinhong, Yarde Melissa, Cvijic Mary Ellen, Mathur Arvind, Li Sha, Shuster David, Khandelwal Purnima, Borowski Virna, Xie Jenny, Obermeier Mary, Fura Aberra, Stefanski Kevin, Cornelius Georgia, Tino Joseph A, Macor John E, Salter-Cid Luisa, Denton Rex, Zhao Qihong, Carter Percy H, Dhar T G Murali
机构信息
Bristol Myers Squibb Company, Research and Early Development, Princeton, New Jersey 08540-4000, United States.
出版信息
ACS Med Chem Lett. 2020 Mar 31;11(6):1221-1227. doi: 10.1021/acsmedchemlett.0c00063. eCollection 2020 Jun 11.
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 , which displayed dose-dependent inhibition of IL-17F production in a mouse IL-2/IL-23 stimulated pharmacodynamic model. In addition, compound 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 (BMS-986251) was selected as a clinically viable developmental candidate.
摘要
设计、合成了新型三环类似物，并将其作为RORγt反向激动剂进行评估。其中几种化合物在IL-17人全血试验中具有强效，并在小鼠药代动力学研究中表现出优异的口服生物利用度。这导致鉴定出化合物，该化合物在小鼠IL-2/IL-23刺激的药效学模型中显示出对IL-17F产生的剂量依赖性抑制作用。此外，在小鼠棘皮症和咪喹莫特诱导的皮肤炎症模型中对化合物进行了研究，结果表明其疗效强劲，与阳性对照相当。由于其整体表现出色，化合物（BMS-986251）被选为具有临床可行性的开发候选药物。
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