American Chemical Society
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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)

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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. Tino
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.