Purine derivatives as potent Bruton鈥檚 tyrosine kinase (BTK) inhibitors for autoimmune diseases

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• 作者：Qing Shi ; ^{qing.shi@bms.com" class="auth_mail} ; Andrew Tebben ; Alaric J. Dyckman ; Hedy Li ; Chunjian Liu ; James Lin ; Steve Spergel ; James R. Burke ; Kim W. McIntyre ; Gilbert C. Olini ; Joann Strnad ; Neha Surti ; Jodi K. Muckelbauer ; Chiehying Chang ; Yongmi An ; Lin Cheng ; Qian Ruan ; Katerina Leftheris ; Percy H. Carter ; Joseph Tino ; George V. De Lucca ; ^{george.delucca@bms.com" class="auth_mail}
• 关键词：BTK ; Autoimmune diseases ; Purine
• 刊名：Bioorganic and Medicinal Chemistry Letters
• 出版年：1 May, 2014
• 年：2014
• 卷：24
• 期：9
• 页码：2206-2211
• 全文大小：3907 K

文摘

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.