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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).

Publication ,  Journal Article
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; Yang, Z ...
Published in: J Med Chem
September 8, 2016

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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Published In

J Med Chem

DOI

EISSN

1520-4804

Publication Date

September 8, 2016

Volume

59

Issue

17

Start / End Page

7915 / 7935

Location

United States

Related Subject Headings

  • Structure-Activity Relationship
  • Quinazolinones
  • Protein-Tyrosine Kinases
  • Permeability
  • Microsomes, Liver
  • Mice
  • Medicinal & Biomolecular Chemistry
  • Macaca fascicularis
  • Humans
  • Dogs
 

Citation

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De Lucca, G. V., Shi, Q., Liu, Q., Batt, D. G., Beaudoin Bertrand, M., Rampulla, R., … Tino, J. A. (2016). 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, 59(17), 7915–7935. https://doi.org/10.1021/acs.jmedchem.6b00722
De Lucca, George V., Qing Shi, Qingjie Liu, Douglas G. Batt, Myra Beaudoin Bertrand, Rick Rampulla, Arvind Mathur, et al. “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 59, no. 17 (September 8, 2016): 7915–35. https://doi.org/10.1021/acs.jmedchem.6b00722.
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. 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):7915–7935.
Journal cover image

Published In

J Med Chem

DOI

EISSN

1520-4804

Publication Date

September 8, 2016

Volume

59

Issue

17

Start / End Page

7915 / 7935

Location

United States

Related Subject Headings

  • Structure-Activity Relationship
  • Quinazolinones
  • Protein-Tyrosine Kinases
  • Permeability
  • Microsomes, Liver
  • Mice
  • Medicinal & Biomolecular Chemistry
  • Macaca fascicularis
  • Humans
  • Dogs