Small Molecule Reversible Inhibitors of Bruton's Tyrosine Kinase (BTK): Structure-Activity Relationships Leading to the Identification of 7-(2-Hydroxypropan-2-yl)-4-[2-methyl-3-(4-oxo-3,4-dihydroquinazolin-3-yl)phenyl]-9H-carbazole-1-carboxamide (BMS-935177).
Bruton's tyrosine kinase (BTK) belongs to the TEC family of nonreceptor tyrosine kinases and plays a critical role in multiple cell types responsible for numerous autoimmune diseases. This article will detail the structure-activity relationships (SARs) leading to a novel second generation series of potent and selective reversible carbazole inhibitors of BTK. With an excellent pharmacokinetic profile as well as demonstrated in vivo activity and an acceptable safety profile, 7-(2-hydroxypropan-2-yl)-4-[2-methyl-3-(4-oxo-3,4-dihydroquinazolin-3-yl)phenyl]-9H-carbazole-1-carboxamide 6 (BMS-935177) was selected to advance into clinical development.
De Lucca, GV; Shi, Q; Liu, Q; Batt, DG; Beaudoin Bertrand, M; Rampulla, R; Mathur, A; Discenza, L; D'Arienzo, C; Dai, J; Obermeier, M; Vickery, R; Zhang, Y; Yang, Z; Marathe, P; Tebben, AJ; Muckelbauer, JK; Chang, CJ; Zhang, H; Gillooly, K; Taylor, T; Pattoli, MA; Skala, S; Kukral, DW; McIntyre, KW; Salter-Cid, L; Fura, A; Burke, JR; Barrish, JC; Carter, PH; Tino, JA
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