三环-碳环 RORγt 反向激动剂-BMS-986313 的发现。
Tricyclic-Carbocyclic RORγt Inverse Agonists-Discovery of BMS-986313.
机构信息
Research and Early Development, Bristol Myers Squibb Company, Princeton, New Jersey 08543-4000, United States.
Department of Discovery Synthesis, Biocon Bristol-Myers Squibb Research Centre, Biocon Park, Bommasandra IV Phase, Jigani Link Road, Bengaluru 560099, India.
出版信息
J Med Chem. 2021 Mar 11;64(5):2714-2724. doi: 10.1021/acs.jmedchem.0c01992. Epub 2021 Feb 16.
SAR efforts directed at identifying RORγt inverse agonists structurally different from our clinical compound (BMS-986251) led to tricyclic-carbocyclic analogues represented by - and culminated in the identification of (BMS-986313), with structural differences distinct from . The X-ray co-crystal structure of with the ligand binding domain of RORγt revealed several key interactions, which are different from . The in vitro and in vivo PK profiles of are described. In addition, we demonstrate robust efficacy of in two preclinical models of psoriasis-the IMQ-induced skin lesion model and the IL-23-induced acanthosis model. The efficacy seen with in these models is comparable to the results observed with .
研究人员致力于寻找与我们的临床化合物（BMS-986251）结构不同的 RORγt 反向激动剂，这导致了三环碳环类似物的出现，其中以 - 为代表，并最终确定了 （BMS-986313），其结构与 明显不同。与 RORγt 的配体结合域的 X 射线共晶结构揭示了几个关键相互作用，这与 不同。描述了 的体外和体内 PK 特征。此外，我们还在两种银屑病的临床前模型——咪喹莫特诱导的皮肤损伤模型和白细胞介素-23 诱导的棘皮症模型中证明了 的强大疗效。在这些模型中， 观察到的疗效与 观察到的结果相当。
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