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)

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

doi:10.1021/acs.jmedchem.6b00722

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. Epub 2016 Aug 26.

Authors

George V De Lucca¹, Qing Shi¹, Qingjie Liu¹, Douglas G Batt¹, Myra Beaudoin Bertrand¹, Rick Rampulla¹, Arvind Mathur¹, Lorell Discenza¹, Celia D'Arienzo¹, Jun Dai¹, Mary Obermeier¹, Rodney Vickery¹, Yingru Zhang¹, Zheng Yang¹, Punit Marathe¹, Andrew J Tebben¹, Jodi K Muckelbauer¹, ChiehYing J Chang¹, Huiping Zhang¹, Kathleen Gillooly¹, Tracy Taylor¹, Mark A Pattoli¹, Stacey Skala¹, Daniel W Kukral¹, Kim W McIntyre¹, Luisa Salter-Cid¹, Aberra Fura¹, James R Burke¹, Joel C Barrish¹, Percy H Carter¹, Joseph A Tino¹

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.

MeSH terms

Administration, Oral
Agammaglobulinaemia Tyrosine Kinase
Animals
Antirheumatic Agents / chemical synthesis
Antirheumatic Agents / chemistry*
Antirheumatic Agents / pharmacokinetics
Antirheumatic Agents / pharmacology
Arthritis, Experimental / drug therapy
Arthritis, Experimental / pathology
Arthritis, Rheumatoid / drug therapy
Arthritis, Rheumatoid / pathology
Biological Availability
Carbazoles / chemical synthesis
Carbazoles / chemistry*
Carbazoles / pharmacokinetics
Carbazoles / pharmacology
Cell Line
Crystallography, X-Ray
Dogs
Humans
Macaca fascicularis
Mice
Microsomes, Liver / metabolism
Permeability
Protein-Tyrosine Kinases / antagonists & inhibitors*
Protein-Tyrosine Kinases / chemistry
Quinazolinones / chemical synthesis
Quinazolinones / chemistry*
Quinazolinones / pharmacokinetics
Quinazolinones / pharmacology
Structure-Activity Relationship

Substances

Antirheumatic Agents
BMS-935177
Carbazoles
Quinazolinones
Protein-Tyrosine Kinases
Agammaglobulinaemia Tyrosine Kinase
BTK protein, human
Btk protein, mouse