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)
dataset
posted on 2016-08-17, 00:00 authored by George V. De Lucca, Qing Shi, Qingjie Liu, Douglas
G. Batt, Myra Beaudoin Bertrand, Rick Rampulla, Arvind Mathur, Lorell Discenza, Celia D’Arienzo, Jun Dai, Mary Obermeier, Rodney Vickery, Yingru Zhang, Zheng Yang, Punit Marathe, Andrew
J. Tebben, Jodi K. Muckelbauer, ChiehYing J. Chang, Huiping Zhang, Kathleen Gillooly, Tracy Taylor, Mark
A. Pattoli, Stacey Skala, Daniel W. Kukral, Kim W. McIntyre, Luisa Salter-Cid, Aberra Fura, James R. Burke, Joel C. Barrish, Percy H. Carter, Joseph A. TinoBruton’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.
