Discovery and preclinical studies of 5-isopropyl-6-(5-methyl-1,3,4-oxadiazol-2-yl)-N-(2-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (BMS-645737), an in vivo active potent VEGFR-2 inhibitor.
We report herein a series of substituted N-(1H-pyrrolo[2,3-b]pyridin-5-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amines as inhibitors of vascular endothelial growth factor receptor-2 tyrosine kinase. Through structure-activity relationship studies, biochemical potency, pharmacokinetics, and kinase selectivity were optimized to afford BMS-645737 (13), a compound with good preclinical in vivo activity against human tumor xenograft models.
Ruel
Réjean
R
Bristol-Myers Squibb, Research and Development, Candiac, Que., Canada J5R 1J1. rruel@ambrilia.com
Thibeault
Carl
C
L'Heureux
Alexandre
A
Martel
Alain
A
Cai
Zhen-Wei
ZW
Wei
Donna
D
Qian
Ligang
L
Barrish
Joel C
JC
Mathur
Arvind
A
D'Arienzo
Celia
C
Hunt
John T
JT
Kamath
Amrita
A
Marathe
Punit
P
Zhang
Yueping
Y
Derbin
George
G
Wautlet
Barri
B
Mortillo
Steven
S
Jeyaseelan
Robert
R
Henley
Benjamin
B
Tejwani
Ravindra
R
Bhide
Rajeev S
RS
Trainor
George L
GL
Fargnoli
Joseph
J
Lombardo
Louis J
LJ
D020533:Angiogenesis Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology*; D000818:Animals; D002460:Cell Line; D065692:Cytochrome P-450 CYP3A Inhibitors; D015195:Drug Design; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors; D006801:Humans; D020128:Inhibitory Concentration 50; D051379:Mice; D008807:Mice, Inbred BALB C; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D011758:Pyrroles / Q000138:chemical synthesis / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014227:Triazines / Q000138:chemical synthesis / Q000494:pharmacology*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors*; D023041:Xenograft Model Antitumor Assays
C529910:5-isopropyl-6-(5-methyl-1,3,4-oxadiazol-2-yl)-N-(2-methyl-1H-pyrrolo(2,3-b)pyridin-5-yl)pyrrolo(2,1-f)(1,2,4)triazin-4-amine; D020533:Angiogenesis Inhibitors; D065692:Cytochrome P-450 CYP3A Inhibitors; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; D011758:Pyrroles; D014227:Triazines; D011505:Protein-Tyrosine Kinases; D040301:Vascular Endothelial Growth Factor Receptor-2