title: Discovery of N-(4-(2-amino-3-chloropyridin-4-yloxy)-3-fluorophenyl)-4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide (BMS-777607), a selective and orally efficacious inhibitor of the Met kinase superfamily.
abstract: Substituted N-(4-(2-aminopyridin-4-yloxy)-3-fluoro-phenyl)-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamides were identified as potent and selective Met kinase inhibitors. Substitution of the pyridine 3-position gave improved enzyme potency, while substitution of the pyridone 4-position led to improved aqueous solubility and kinase selectivity. Analogue 10 demonstrated complete tumor stasis in a Met-dependent GTL-16 human gastric carcinoma xenograft model following oral administration. Because of its excellent in vivo efficacy and favorable pharmacokinetic and preclinical safety profiles, 10 has been advanced into phase I clinical trials.
authors.affiliation: Bristol-Myers Squibb Research and Development, Princeton, New Jersey, 08543-4000, USA. gretchen.schroeder@bms.com
authors.forename: Gretchen M
authors.initials: GM
authors.lastname: Schroeder
authors.forename: Yongmi
authors.initials: Y
authors.lastname: An
authors.forename: Zhen-Wei
authors.initials: ZW
authors.lastname: Cai
authors.forename: Xiao-Tao
authors.initials: XT
authors.lastname: Chen
authors.forename: Cheryl
authors.initials: C
authors.lastname: Clark
authors.forename: Lyndon A M
authors.initials: LA
authors.lastname: Cornelius
authors.forename: Jun
authors.initials: J
authors.lastname: Dai
authors.forename: Johnni
authors.initials: J
authors.lastname: Gullo-Brown
authors.forename: Ashok
authors.initials: A
authors.lastname: Gupta
authors.forename: Benjamin
authors.initials: B
authors.lastname: Henley
authors.forename: John T
authors.initials: JT
authors.lastname: Hunt
authors.forename: Robert
authors.initials: R
authors.lastname: Jeyaseelan
authors.forename: Amrita
authors.initials: A
authors.lastname: Kamath
authors.forename: Kyoung
authors.initials: K
authors.lastname: Kim
authors.forename: Jonathan
authors.initials: J
authors.lastname: Lippy
authors.forename: Louis J
authors.initials: LJ
authors.lastname: Lombardo
authors.forename: Veeraswamy
authors.initials: V
authors.lastname: Manne
authors.forename: Simone
authors.initials: S
authors.lastname: Oppenheimer
authors.forename: John S
authors.initials: JS
authors.lastname: Sack
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Schmidt
authors.forename: Guoxiang
authors.initials: G
authors.lastname: Shen
authors.forename: Kevin
authors.initials: K
authors.lastname: Stefanski
authors.forename: John S
authors.initials: JS
authors.lastname: Tokarski
authors.forename: George L
authors.initials: GL
authors.lastname: Trainor
authors.forename: Barri S
authors.initials: BS
authors.lastname: Wautlet
authors.forename: Donna
authors.initials: D
authors.lastname: Wei
authors.forename: David K
authors.initials: DK
authors.lastname: Williams
authors.forename: Yingru
authors.initials: Y
authors.lastname: Zhang
authors.forename: Yueping
authors.initials: Y
authors.lastname: Zhang
authors.forename: Joseph
authors.initials: J
authors.lastname: Fargnoli
authors.forename: Robert M
authors.initials: RM
authors.lastname: Borzilleri
mesh_terms: D000284:Administration, Oral; D000631:Aminopyridines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D045744:Cell Line, Tumor; D018360:Crystallography, X-Ray; D004095:Dihydropyridines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D004285:Dogs; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D008958:Models, Molecular; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors*; D011728:Pyridones / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D012995:Solubility; D013329:Structure-Activity Relationship; D023041:Xenograft Model Antitumor Assays
chemical_list: D000631:Aminopyridines; D000970:Antineoplastic Agents; D004095:Dihydropyridines; C550356:N-(4-(2-amino-3-chloropyridin-4-yloxy)-3-fluorophenyl)-4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide; D011728:Pyridones; D019859:Proto-Oncogene Proteins c-met