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)

  • J Med Chem. 2016 Sep 8;59(17):7915-35. doi: 10.1021/acs.jmedchem.6b00722.
George V De Lucca  1 ,  Qing Shi  1 ,  Qingjie Liu  1 ,  Douglas G Batt  1 ,  Myra Beaudoin Bertrand  1 ,  Rick Rampulla  1 ,  Arvind Mathur  1 ,  Lorell Discenza  1 ,  Celia D'Arienzo  1 ,  Jun Dai  1 ,  Mary Obermeier  1 ,  Rodney Vickery  1 ,  Yingru Zhang  1 ,  Zheng Yang  1 ,  Punit Marathe  1 ,  Andrew J Tebben  1 ,  Jodi K Muckelbauer  1 ,  ChiehYing J Chang  1 ,  Huiping Zhang  1 ,  Kathleen Gillooly  1 ,  Tracy Taylor  1 ,  Mark A Pattoli  1 ,  Stacey Skala  1 ,  Daniel W Kukral  1 ,  Kim W McIntyre  1 ,  Luisa Salter-Cid  1 ,  Aberra Fura  1 ,  James R Burke  1 ,  Joel C Barrish  1 ,  Percy H Carter  1 ,  Joseph A Tino  1
Affiliations
  • 1. Immunosciences Discovery Chemistry, ‡Immunoscience Discovery Biology, §Molecular Structure and Design, Molecular Discovery Technologies, ∥Metabolism and Pharmacokinetic Department, Pharmaceutical Candidate Optimization, and ⊥ECTR/CTTO Imaging Department, Bristol-Myers Squibb Research and Development , P.O. Box 4000, Princeton, New Jersey 08543, United States.
PMID: 27531604 DOI: 10.1021/acs.jmedchem.6b00722
Abstract

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.

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