title: Discovery and evaluation of N-cyclopropyl- 2,4-difluoro-5-((2-(pyridin-2-ylamino)thiazol-5- ylmethyl)amino)benzamide (BMS-605541), a selective and orally efficacious inhibitor of vascular endothelial growth factor receptor-2.
abstract: Substituted 3-((2-(pyridin-2-ylamino)thiazol-5-ylmethyl)amino)benzamides were identified as potent and selective inhibitors of vascular endothelial growth factor receptor-2 (VEGFR-2) kinase activity. The enzyme kinetics associated with the VEGFR-2 inhibition of 14 (Ki=49+/-9 nM) confirmed that the aminothiazole-based analogues are competitive with ATP. Analogue 14 demonstrated excellent kinase selectivity, favorable pharmacokinetic properties in multiple species, and robust in vivo efficacy in human lung and colon carcinoma xenograft models.
authors.affiliation: Bristol-Myers Squibb Pharmaceutical Research Institute, P.O. Box 4000, Princeton, New Jersey 08543-4000, USA. robert.borzilleri@bms.com
authors.forename: Robert M
authors.initials: RM
authors.lastname: Borzilleri
authors.forename: Rajeev S
authors.initials: RS
authors.lastname: Bhide
authors.forename: Joel C
authors.initials: JC
authors.lastname: Barrish
authors.forename: Celia J
authors.initials: CJ
authors.lastname: D'Arienzo
authors.forename: George M
authors.initials: GM
authors.lastname: Derbin
authors.forename: Joseph
authors.initials: J
authors.lastname: Fargnoli
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: Daniel W
authors.initials: DW
authors.lastname: Kukral
authors.forename: Punit
authors.initials: P
authors.lastname: Marathe
authors.forename: Steve
authors.initials: S
authors.lastname: Mortillo
authors.forename: Ligang
authors.initials: L
authors.lastname: Qian
authors.forename: John S
authors.initials: JS
authors.lastname: Tokarski
authors.forename: Barri S
authors.initials: BS
authors.lastname: Wautlet
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Zheng
authors.forename: Louis J
authors.initials: LJ
authors.lastname: Lombardo
mesh_terms: D000284:Administration, Oral; D000631:Aminopyridines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D020533:Angiogenesis Inhibitors / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D001665:Binding Sites; D049109:Cell Proliferation; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects; D004730:Endothelium, Vascular / Q000166:cytology; D006801:Humans; D066298:In Vitro Techniques; D008252:Macaca fascicularis; D051379:Mice; D008819:Mice, Nude; D008958:Models, Molecular; D051381:Rats; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D014471:Umbilical Veins / Q000166:cytology; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors* / Q000737:chemistry; D023041:Xenograft Model Antitumor Assays
chemical_list: D000631:Aminopyridines; D020533:Angiogenesis Inhibitors; C512435:N-cyclopropyl-2,4-difluoro-5-((2-(pyridin-2-ylamino)thiazol-5-ylmethyl)amino)benzamide; D013844:Thiazoles; D040301:Vascular Endothelial Growth Factor Receptor-2