利用旋转稳定的阻转异构体提高药效：BTK的吡啶并嘧啶二酮-咔唑抑制剂的发现
Driving Potency with Rotationally Stable Atropisomers: Discovery of Pyridopyrimidinedione-Carbazole Inhibitors of BTK.
作者信息
Srivastava Anurag S, Ko Soo, Watterson Scott H, Pattoli Mark A, Skala Stacey, Cheng Lihong, Obermeier Mary T, Vickery Rodney, Discenza Lorell N, D'Arienzo Celia J, Gillooly Kathleen M, Taylor Tracy L, Pulicicchio Claudine, McIntyre Kim W, Yip Shiuhang, Li Peng, Sun Dawn, Wu Dauh-Rurng, Dai Jun, Wang Chunlei, Zhang Yingru, Wang Bei, Pawluczyk Joseph, Kempson James, Zhao Rulin, Hou Xiaoping, Rampulla Richard, Mathur Arvind, Galella Michael A, Salter-Cid Luisa, Barrish Joel C, Carter Percy H, Fura Aberra, Burke James R, Tino Joseph A
机构信息
Bristol Myers Squibb Research and Early Development, P.O. Box 4000, Princeton, New Jersey 08543, United States.
出版信息
ACS Med Chem Lett. 2020 Sep 16;11(11):2195-2203. doi: 10.1021/acsmedchemlett.0c00335. eCollection 2020 Nov 12.
Bruton's tyrosine kinase (BTK) has been shown to play a key role in the pathogenesis of autoimmunity. Therefore, the inhibition of the kinase activity of BTK with a small molecule inhibitor could offer a breakthrough in the clinical treatment of many autoimmune diseases. This Letter describes the discovery of BMS-986143 through systematic structure-activity relationship (SAR) development. This compound benefits from defined chirality derived from two rotationally stable atropisomeric axes, providing a potent and selective single atropisomer with desirable efficacy and tolerability profiles.
布鲁顿酪氨酸激酶（BTK）已被证明在自身免疫性疾病的发病机制中起关键作用。因此，用小分子抑制剂抑制BTK的激酶活性可能为许多自身免疫性疾病的临床治疗带来突破。本信函描述了通过系统的构效关系（SAR）开发发现BMS-986143的过程。该化合物得益于源自两个旋转稳定的阻转异构轴的特定手性，提供了一种具有理想疗效和耐受性的强效且选择性的单一阻转异构体。
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