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Driving Potency with Rotationally Stable Atropisomers: Discovery of Pyridopyrimidinedione-Carbazole Inhibitors of BTK
ACS Medicinal Chemistry Letters ( IF 3.5 ) Pub Date : 2020-09-16 , DOI: 10.1021/acsmedchemlett.0c00335 Anurag S Srivastava 1 , Soo Ko 1 , Scott H Watterson 1 , Mark A Pattoli 1 , Stacey Skala 1 , Lihong Cheng 1 , Mary T Obermeier 1 , Rodney Vickery 1 , Lorell N Discenza 1 , Celia J D'Arienzo 1 , Kathleen M Gillooly 1 , Tracy L Taylor 1 , Claudine Pulicicchio 1 , Kim W McIntyre 1 , Shiuhang Yip 1 , Peng Li 1 , Dawn Sun 1 , Dauh-Rurng Wu 1 , Jun Dai 1 , Chunlei Wang 1 , Yingru Zhang 1 , Bei Wang 1 , Joseph Pawluczyk 1 , James Kempson 1 , Rulin Zhao 1 , Xiaoping Hou 1 , Richard Rampulla 1 , Arvind Mathur 1 , Michael A Galella 1 , Luisa Salter-Cid 1 , Joel C Barrish 1 , Percy H Carter 1 , Aberra Fura 1 , James R Burke 1 , Joseph A Tino 1
ACS Medicinal Chemistry Letters ( IF 3.5 ) Pub Date : 2020-09-16 , DOI: 10.1021/acsmedchemlett.0c00335 Anurag S Srivastava 1 , Soo Ko 1 , Scott H Watterson 1 , Mark A Pattoli 1 , Stacey Skala 1 , Lihong Cheng 1 , Mary T Obermeier 1 , Rodney Vickery 1 , Lorell N Discenza 1 , Celia J D'Arienzo 1 , Kathleen M Gillooly 1 , Tracy L Taylor 1 , Claudine Pulicicchio 1 , Kim W McIntyre 1 , Shiuhang Yip 1 , Peng Li 1 , Dawn Sun 1 , Dauh-Rurng Wu 1 , Jun Dai 1 , Chunlei Wang 1 , Yingru Zhang 1 , Bei Wang 1 , Joseph Pawluczyk 1 , James Kempson 1 , Rulin Zhao 1 , Xiaoping Hou 1 , Richard Rampulla 1 , Arvind Mathur 1 , Michael A Galella 1 , Luisa Salter-Cid 1 , Joel C Barrish 1 , Percy H Carter 1 , Aberra Fura 1 , James R Burke 1 , Joseph A Tino 1
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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.
中文翻译：
旋转稳定阻转异构体的驱动效力：发现 BTK 的吡啶并嘧啶二酮-咔唑抑制剂
布鲁顿酪氨酸激酶 (BTK) 已被证明在自身免疫的发病机制中起关键作用。因此，用小分子抑制剂抑制BTK的激酶活性可以为许多自身免疫性疾病的临床治疗提供突破。本信函描述了通过系统构效关系 (SAR) 开发发现 BMS-986143。该化合物受益于源自两个旋转稳定的阻转异构体轴的确定手性，提供具有理想功效和耐受性的有效且选择性的单一阻转异构体。
更新日期：2020-11-12
中文翻译：
旋转稳定阻转异构体的驱动效力：发现 BTK 的吡啶并嘧啶二酮-咔唑抑制剂
布鲁顿酪氨酸激酶 (BTK) 已被证明在自身免疫的发病机制中起关键作用。因此，用小分子抑制剂抑制BTK的激酶活性可以为许多自身免疫性疾病的临床治疗提供突破。本信函描述了通过系统构效关系 (SAR) 开发发现 BMS-986143。该化合物受益于源自两个旋转稳定的阻转异构体轴的确定手性，提供具有理想功效和耐受性的有效且选择性的单一阻转异构体。
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