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).

Journal Article (Journal Article)

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.

Full Text

Duke Authors

Cited Authors

  • 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

Published Date

  • September 8, 2016

Published In

Volume / Issue

  • 59 / 17

Start / End Page

  • 7915 - 7935

PubMed ID

  • 27531604

Electronic International Standard Serial Number (EISSN)

  • 1520-4804

Digital Object Identifier (DOI)

  • 10.1021/acs.jmedchem.6b00722


  • eng

Conference Location

  • United States