Bruton’s tyrosine kinase (BTK), a non-receptor tyrosine kinase, is a member of the Tec family of kinases.  BTK plays an essential role in B cell receptor (BCR)-mediated signaling as well as Fcg receptor signaling in monocytes and Fce receptor signaling in mast cells and basophils, all of which have implications in the pathophysiology of autoimmune disease.  As a result, inhibition of BTK is anticipated to provide an effective strategy for the clinical treatment of autoimmune diseases such as rheumatoid arthritis and lupus.  This presentation will detail the structure-activity relationships (SAR) leading to a novel series of highly potent and selective carbazole and tetrahydrocarbazole based, reversible inhibitors of BTK.  Of particular interest is that two atropisomeric centers were rotationally locked to provide a single, stable atropisomer, resulting in enhanced potency and selectivity as well as a reduction in safety liabilities.  With excellent in vivo efficacy and a very desirable tolerability profile, BMS-986142 has advanced into clinical studies.

Discovery of BMS-986142: A reversible inhibitor of Bruton’s Tyrosine Kinase (BTK) conformationally constrained by two locked atropisomers

253rd National Meeting (2017)

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