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.
Bristol-Myers Squibb, Pharmaceutical Research Institute, Princeton, New Jersey 08543-4000, USA. rajeev.bhide@bms.com
Rajeev S
RS
Bhide
Zhen-Wei
ZW
Cai
Yong-Zheng
YZ
Zhang
Ligang
L
Qian
Donna
D
Wei
Stephanie
S
Barbosa
Louis J
LJ
Lombardo
Robert M
RM
Borzilleri
Xiaoping
X
Zheng
Laurence I
LI
Wu
Joel C
JC
Barrish
Soong-Hoon
SH
Kim
Kenneth
K
Leavitt
Arvind
A
Mathur
Leslie
L
Leith
Sam
S
Chao
Barri
B
Wautlet
Steven
S
Mortillo
Robert
R
Jeyaseelan
Daniel
D
Kukral
John T
JT
Hunt
Amrita
A
Kamath
Aberra
A
Fura
Viral
V
Vyas
Punit
P
Marathe
Celia
C
D'Arienzo
George
G
Derbin
Joseph
J
Fargnoli
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