title: 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).
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.
authors.affiliation: 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.
authors.forename: George V
authors.initials: GV
authors.lastname: De Lucca
authors.affiliation: 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.
authors.forename: Qing
authors.initials: Q
authors.lastname: Shi
authors.affiliation: 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.
authors.forename: Qingjie
authors.initials: Q
authors.lastname: Liu
authors.affiliation: 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.
authors.forename: Douglas G
authors.initials: DG
authors.lastname: Batt
authors.affiliation: 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.
authors.forename: Myra
authors.initials: M
authors.lastname: Beaudoin Bertrand
authors.affiliation: 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.
authors.forename: Rick
authors.initials: R
authors.lastname: Rampulla
authors.affiliation: 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.
authors.forename: Arvind
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authors.lastname: Mathur
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authors.forename: Lorell
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authors.lastname: Discenza
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authors.forename: Celia
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authors.lastname: D'Arienzo
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authors.lastname: Dai
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authors.forename: Mary
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authors.lastname: Obermeier
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authors.lastname: Vickery
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authors.forename: Yingru
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authors.lastname: Zhang
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authors.forename: Zheng
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authors.lastname: Yang
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authors.forename: Punit
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authors.lastname: Marathe
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authors.forename: Andrew J
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authors.lastname: Tebben
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authors.lastname: Muckelbauer
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authors.forename: ChiehYing J
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authors.lastname: Chang
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authors.forename: Huiping
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authors.lastname: Pattoli
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authors.lastname: Skala
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authors.forename: Aberra
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authors.lastname: Fura
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authors.forename: James R
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authors.lastname: Burke
authors.affiliation: 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.
authors.forename: Joel C
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authors.lastname: Barrish
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authors.lastname: Carter
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authors.lastname: Tino
mesh_terms: D000284:Administration, Oral; D000077329:Agammaglobulinaemia Tyrosine Kinase; D000818:Animals; D018501:Antirheumatic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D001169:Arthritis, Experimental / Q000188:drug therapy / Q000473:pathology; D001172:Arthritis, Rheumatoid / Q000188:drug therapy / Q000473:pathology; D001682:Biological Availability; D002227:Carbazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D002460:Cell Line; D018360:Crystallography, X-Ray; D004285:Dogs; D006801:Humans; D008252:Macaca fascicularis; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism; D010539:Permeability; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D052999:Quinazolinones / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D018501:Antirheumatic Agents; C000621124:BMS-935177; D002227:Carbazoles; D052999:Quinazolinones; D011505:Protein-Tyrosine Kinases; D000077329:Agammaglobulinaemia Tyrosine Kinase; C000625949:BTK protein, human; C000625951:Btk protein, mouse