Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
10592639 | Bioorganic & Medicinal Chemistry Letters | 2014 | 6 Pages |
Abstract
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.
Keywords
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Physical Sciences and Engineering
Chemistry
Organic Chemistry
Authors
Qing Shi, 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,