Discovery and preclinical studies of (R)-1-(4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-5- methylpyrrolo[2,1-f][1,2,4]triazin-6-yloxy)propan- 2-ol (BMS-540215), an in vivo active potent VEGFR-2 inhibitor.
A series of substituted 4-(4-fluoro-1H-indol-5-yloxy)pyrrolo[2,1-f][1,2,4]triazine-based inhibitors of vascular endothelial growth factor receptor-2 kinase is reported. Structure-activity relationship studies revealed that a methyl group at the 5-position and a substituted alkoxy group at the 6-position of the pyrrolo[2,1-f][1,2,4]triazine core gave potent compounds. Biochemical potency, kinase selectivity, and pharmacokinetics of the series were optimized and in vitro safety liabilities were minimized to afford BMS-540215 (12), which demonstrated robust preclinical in vivo activity in human tumor xenograft models. The l-alanine prodrug of 12, BMS-582664 (21), is currently under evaluation in clinical trials for the treatment of solid tumors.
Bhide
Rajeev S
RS
Bristol-Myers Squibb, Pharmaceutical Research Institute, Princeton, New Jersey 08543-4000, USA. rajeev.bhide@bms.com
Cai
Zhen-Wei
ZW
Zhang
Yong-Zheng
YZ
Qian
Ligang
L
Wei
Donna
D
Barbosa
Stephanie
S
Lombardo
Louis J
LJ
Borzilleri
Robert M
RM
Zheng
Xiaoping
X
Wu
Laurence I
LI
Barrish
Joel C
JC
Kim
Soong-Hoon
SH
Leavitt
Kenneth
K
Mathur
Arvind
A
Leith
Leslie
L
Chao
Sam
S
Wautlet
Barri
B
Mortillo
Steven
S
Jeyaseelan
Robert
R
Kukral
Daniel
D
Hunt
John T
JT
Kamath
Amrita
A
Fura
Aberra
A
Vyas
Viral
V
Marathe
Punit
P
D'Arienzo
Celia
C
Derbin
George
G
Fargnoli
Joseph
J
D000409:Alanine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D020533:Angiogenesis Inhibitors / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D045744:Cell Line, Tumor; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D011355:Prodrugs / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D011758:Pyrroles / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014183:Transplantation, Heterologous; D014227:Triazines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors*
D020533:Angiogenesis Inhibitors; D011355:Prodrugs; D011758:Pyrroles; D014227:Triazines; C509922:brivanib; D040301:Vascular Endothelial Growth Factor Receptor-2; D000409:Alanine