布鲁顿酪氨酸激酶
广告
化学
酪氨酸激酶
嘌呤类似物
体内
激酶
细胞生长
嘌呤
生物化学
立体化学
药理学
体外
酶
信号转导
生物
生物技术
作者
Qing Shi,Andrew J. Tebben,Alaric J. Dyckman,Hedy Li,Chunjian Liu,James Lin,Steven H. Spergel,James R. Burke,Kim W. McIntyre,Gilbert C. Olini,Joann Strnad,Neha Surti,J.K. Muckelbauer,Chiehying Chang,Yongmi An,Lin Cheng,Qian Ruan,Katerina Leftheris,Percy H. Carter,Joseph A. Tino,George V. De Lucca
标识
DOI:10.1016/j.bmcl.2014.02.075
摘要
Investigation of various heterocyclic core isosteres of imidazopyrazines 1 & 2 yielded purine derivatives 3 & 8 as potent and selective BTK inhibitors. Subsequent SAR studies of the purine series led to the discovery of 20 as a leading compound. Compound 20 is very selective when screened against a panel of 400 kinases and is a potent inhibitor in cellular assays of human B cell function including B-Cell proliferation and CD86 cell surface expression and exhibited in vivo efficacy in a mouse PCA model. Its X-ray co-crystal structure with BTK shows that the high selectivity is gained from filling a BTK specific lipophilic pocket. However, physical and ADME properties leading to low oral exposure hindered further development.
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