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)

J Med Chem. 2008 Mar 27;51(6):1976-80. doi: 10.1021/jm7013309. Epub 2008 Feb 21.

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.

MeSH terms

  • Administration, Oral
  • Alanine / analogs & derivatives
  • Animals
  • Biological Availability
  • Carcinoma / drug therapy*
  • Cell Proliferation / drug effects
  • Clinical Trials, Phase II as Topic
  • Drug Design
  • Drug Evaluation, Preclinical
  • Humans
  • Intestines / drug effects
  • Liver / drug effects
  • Lung Neoplasms / drug therapy*
  • Mice
  • Microsomes / drug effects
  • Molecular Structure
  • Prodrugs / chemical synthesis
  • Prodrugs / chemistry
  • Prodrugs / pharmacology*
  • Protein Kinase Inhibitors / chemical synthesis
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / pharmacology*
  • Pyrroles / chemical synthesis
  • Pyrroles / chemistry
  • Pyrroles / pharmacology*
  • Receptor, Fibroblast Growth Factor, Type 1 / antagonists & inhibitors*
  • Solubility
  • Stereoisomerism
  • Triazines / chemical synthesis
  • Triazines / chemistry
  • Triazines / pharmacology*
  • Vascular Endothelial Growth Factor Receptor-2 / antagonists & inhibitors*
  • Water / chemistry
  • Xenograft Model Antitumor Assays

Substances

  • Prodrugs
  • Protein Kinase Inhibitors
  • Pyrroles
  • Triazines
  • Water
  • brivanib
  • Receptor, Fibroblast Growth Factor, Type 1
  • Vascular Endothelial Growth Factor Receptor-2
  • Alanine