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, George V.,Shi, Qing,Liu, Qingjie,Batt, Douglas G.,Beaudoin Bertrand, Myra,Rampulla, Rick,Mathur, Arvind,Discenza, Lorell,D'Arienzo, Celia,Dai, Jun,Obermeier, Mary,Vickery, Rodney,Zhang, Yingru,Yang, Zheng,Marathe, Punit,Tebben, Andrew J.,Muckelbauer, Jodi K.,Chang, Chiehying J.,Zhang, Huiping,Gillooly, Kathleen,Taylor, Tracy,Pattoli, Mark A.,Skala, Stacey,Kukral, Daniel W.,McIntyre, Kim W.,Salter-Cid, Luisa,Fura, Aberra,Burke, James R.,Barrish, Joel C.,Carter, Percy H.,Tino, Joseph A.
CARBAZOLE CARBOXAMIDE COMPOUNDS USEFUL AS KINASE INHIBITORS
Compounds having the formula (I), and enantiomers, and diastereomers, pharmaceutically-acceptable salts, thereof, are useful as kinase modulators, including Btk modulation.
-
Page/Page column 31
(2010/07/04)
More Articles about upstream products of 1231891-09-0