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.
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.
Borzilleri
Robert M
RM
Bristol-Myers Squibb Pharmaceutical Research Institute, P.O. Box 4000, Princeton, New Jersey 08543-4000, USA. robert.borzilleri@bms.com
Bhide
Rajeev S
RS
Barrish
Joel C
JC
D'Arienzo
Celia J
CJ
Derbin
George M
GM
Fargnoli
Joseph
J
Hunt
John T
JT
Jeyaseelan
Robert
R
Kamath
Amrita
A
Kukral
Daniel W
DW
Marathe
Punit
P
Mortillo
Steve
S
Qian
Ligang
L
Tokarski
John S
JS
Wautlet
Barri S
BS
Zheng
Xiaoping
X
Lombardo
Louis J
LJ
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
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