2. Academic Validation
  3. 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)

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

Affiliation

  • 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.

Figures
Products