Conversion of carbazole carboxamide based reversible inhibitors of Bruton's tyrosine kinase (BTK) into potent, selective irreversible inhibitors in the carbazole, tetrahydrocarbazole, and a new 2, 3-dimethylindole series. Issue 18 (1st October 2018)

• Record Type: Journal Article
• Authors: Liu, Qingjie; Batt, Douglas G.; Chaudhry, Charu; Lippy, Jonathan S.; Pattoli, Mark A.; Surti, Neha; Xu, Songmei; Carter, Percy H.; Burke, James R.; Tino, Joseph A.
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 28:Issue 18(2018)
• Page Start: 3080
• Page End: 3084
• Publication Date: 2018-10-01
• Subjects: Bruton's tyrosine kinase -- BTK -- Indole carboxamide -- Carbazole -- Irreversible inhibitor; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2018.07.041
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: Highlights: Electrophilic groups increased potency and selectivity of carbazole BTK inhibitors. Related indole analogs retained this potency and further increased selectivity. Irreversible inhibition was demonstrated using a dialysis assay. Better physicochemical characteristics accompanied the improved biochemical profile. Abstract: Incorporation of a suitably-placed electrophilic group transformed a series of reversible BTK inhibitors based on carbazole-1-carboxamide and tetrahydrocarbazole-1-carboxamide into potent, irreversible inhibitors. Removal of one ring from the core of these compounds provided a potent irreversible series of 2, 3-dimethylindole-7-carboxamides having excellent potency and improved selectivity, with the additional advantages of reduced lipophilicity and molecular weight.