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
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DOI：
10.1021/acsmedchemlett.0c00063
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发表时间：
2020-06-11
影响因子：
4.2
通讯作者：
Dhar, T. G. Murali
中科院分区：
文献类型：
--
作者：
Cherney, Robert J.;Cornelius, Lyndon A. M.;Dhar, T. G. Murali
新型三环类似物的设计，合成，并作为ROR γ t反向激动剂进行评价。这些化合物中的几种在IL-17人全血测定中是有效的，并且在小鼠药代动力学研究中表现出优异的口服生物利用度。这导致化合物5的鉴定，其在小鼠IL-2/IL-23刺激的药效学模型中显示出对IL-17 F产生的剂量依赖性抑制。此外，在小鼠棘皮病和咪喹莫特诱导的皮肤炎症模型中研究了化合物5，其中其表现出与阳性对照相当的稳健功效。由于该优异的总体特征，选择化合物5（BMS-986251）作为临床上可行的开发候选物。
Novel tricyclic analogues were designed, synthesized, and evaluated as ROR gamma t 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.