Discovery of brivanib alaninate ((S)-((R)-1-(4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-yloxy)propan-2-yl)2-aminopropanoate), a novel prodrug of dual vascular endothelial growth factor receptor-2 and fibroblast growth factor receptor-1 kinase inhibitor (BMS-540215).
A series of amino acid ester prodrugs of the dual VEGFR-2/FGFR-1 kinase inhibitor 1 (BMS-540215) was prepared in an effort to improve the aqueous solubility and oral bioavailability of the parent compound. These prodrugs were evaluated for their ability to liberate parent drug 1 in in vitro and in vivo systems. The l-alanine prodrug 8 (also known as brivanib alaninate/BMS-582664) was selected as a development candidate and is presently in phase II clinical trials.
Cai
Zhen-wei
ZW
Bristol-Myers Squibb Research and Development, Princeton, NJ 08543, USA. zhenwei.cai@bms.com
Zhang
Yongzheng
Y
Borzilleri
Robert M
RM
Qian
Ligang
L
Barbosa
Stephanie
S
Wei
Donna
D
Zheng
Xiaoping
X
Wu
Lawrence
L
Fan
Junying
J
Shi
Zhongping
Z
Wautlet
Barri S
BS
Mortillo
Steve
S
Jeyaseelan
Robert
R
Kukral
Daniel W
DW
Kamath
Amrita
A
Marathe
Punit
P
D'Arienzo
Celia
C
Derbin
George
G
Barrish
Joel C
JC
Robl
Jeffrey A
JA
Hunt
John T
JT
Lombardo
Louis J
LJ
Fargnoli
Joseph
J
Bhide
Rajeev S
RS
D000284:Administration, Oral; D000409:Alanine / Q000031:analogs & derivatives; D000818:Animals; D001682:Biological Availability; D002277:Carcinoma / Q000188:drug therapy*; D049109:Cell Proliferation / Q000187:drug effects; D017322:Clinical Trials, Phase II as Topic; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D006801:Humans; D007422:Intestines / Q000187:drug effects; D008099:Liver / Q000187:drug effects; D008175:Lung Neoplasms / Q000188:drug therapy*; D051379:Mice; D008861:Microsomes / Q000187:drug effects; D015394:Molecular Structure; D011355:Prodrugs / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011758:Pyrroles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000037:antagonists & inhibitors*; D012995:Solubility; D013237:Stereoisomerism; D014227:Triazines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors*; D014867:Water / Q000737:chemistry; D023041:Xenograft Model Antitumor Assays
D011355:Prodrugs; D047428:Protein Kinase Inhibitors; D011758:Pyrroles; D014227:Triazines; D014867:Water; C509922:brivanib; D051496:Receptor, Fibroblast Growth Factor, Type 1; D040301:Vascular Endothelial Growth Factor Receptor-2; D000409:Alanine