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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).
De Lucca, George V; Shi, Qing; Liu, Qingjie; Batt, Douglas G; Beaudoin Bertrand, Myra; Rampulla, Rick; Mathur, Arvind; Discenza, Lorell; D'Arienzo, Celia; Dai, Jun; Obermeier, Mary; Vickery, Rodney; Zhang, Yingru; Yang, Zheng; Marathe, Punit; Tebben, Andrew J; Muckelbauer, Jodi K; Chang, ChiehYing J; Zhang, Huiping; Gillooly, Kathleen; Taylor, Tracy; Pattoli, Mark A; Skala, Stacey; Kukral, Daniel W; McIntyre, Kim W; Salter-Cid, Luisa; Fura, Aberra; Burke, James R; Barrish, Joel C; Carter, Percy H; Tino, Joseph A.
Afiliação
  • De Lucca GV; 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 Develop
  • Shi Q; 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 Develop
  • Liu Q; 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 Develop
  • Batt DG; 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 Develop
  • Beaudoin Bertrand M; 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 Develop
  • Rampulla R; 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 Develop
  • Mathur A; 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 Develop
  • Discenza L; 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 Develop
  • D'Arienzo C; 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 Develop
  • Dai J; 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 Develop
  • Obermeier M; 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 Develop
  • Vickery R; 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 Develop
  • Zhang Y; 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 Develop
  • Yang Z; 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 Develop
  • Marathe P; 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 Develop
  • Tebben AJ; 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 Develop
  • Muckelbauer JK; 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 Develop
  • Chang CJ; 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 Develop
  • Zhang H; 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 Develop
  • Gillooly K; 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 Develop
  • Taylor T; 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 Develop
  • Pattoli MA; 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 Develop
  • Skala S; 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 Develop
  • Kukral DW; 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 Develop
  • McIntyre KW; 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 Develop
  • Salter-Cid L; 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 Develop
  • Fura A; 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 Develop
  • Burke JR; 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 Develop
  • Barrish JC; 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 Develop
  • Carter PH; 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 Develop
  • Tino JA; 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 Develop
J Med Chem ; 59(17): 7915-35, 2016 09 08.
Article em En | MEDLINE | ID: mdl-27531604
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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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Proteínas Tirosina Quinases / Carbazóis / Antirreumáticos / Quinazolinonas Tipo de estudo: Diagnostic_studies Limite: Animals / Humans Idioma: En Revista: J Med Chem Assunto da revista: QUIMICA Ano de publicação: 2016 Tipo de documento: Article
Texto completo
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Proteínas Tirosina Quinases / Carbazóis / Antirreumáticos / Quinazolinonas Tipo de estudo: Diagnostic_studies Limite: Animals / Humans Idioma: En Revista: J Med Chem Assunto da revista: QUIMICA Ano de publicação: 2016 Tipo de documento: Article