title: 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).
abstract: 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.
authors.affiliation: Bristol-Myers Squibb Research and Development, Princeton, NJ 08543, USA. zhenwei.cai@bms.com
authors.forename: Zhen-wei
authors.initials: ZW
authors.lastname: Cai
authors.forename: Yongzheng
authors.initials: Y
authors.lastname: Zhang
authors.forename: Robert M
authors.initials: RM
authors.lastname: Borzilleri
authors.forename: Ligang
authors.initials: L
authors.lastname: Qian
authors.forename: Stephanie
authors.initials: S
authors.lastname: Barbosa
authors.forename: Donna
authors.initials: D
authors.lastname: Wei
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Zheng
authors.forename: Lawrence
authors.initials: L
authors.lastname: Wu
authors.forename: Junying
authors.initials: J
authors.lastname: Fan
authors.forename: Zhongping
authors.initials: Z
authors.lastname: Shi
authors.forename: Barri S
authors.initials: BS
authors.lastname: Wautlet
authors.forename: Steve
authors.initials: S
authors.lastname: Mortillo
authors.forename: Robert
authors.initials: R
authors.lastname: Jeyaseelan
authors.forename: Daniel W
authors.initials: DW
authors.lastname: Kukral
authors.forename: Amrita
authors.initials: A
authors.lastname: Kamath
authors.forename: Punit
authors.initials: P
authors.lastname: Marathe
authors.forename: Celia
authors.initials: C
authors.lastname: D'Arienzo
authors.forename: George
authors.initials: G
authors.lastname: Derbin
authors.forename: Joel C
authors.initials: JC
authors.lastname: Barrish
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Robl
authors.forename: John T
authors.initials: JT
authors.lastname: Hunt
authors.forename: Louis J
authors.initials: LJ
authors.lastname: Lombardo
authors.forename: Joseph
authors.initials: J
authors.lastname: Fargnoli
authors.forename: Rajeev S
authors.initials: RS
authors.lastname: Bhide
mesh_terms: 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
chemical_list: 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