Synthesis and biopharmaceutical studies of JLTN as potential dasatinib prodrug

Chem Pharm Bull (Tokyo). 2013;61(8):877-81. doi: 10.1248/cpb.c13-00248. Epub 2013 May 16.

Abstract

Dasatinib was identified as a potent orally administered Src/Abl kinase inhibitor with excellent antiproliferative activity against Philadelphia chromosome-positive chronic myelogenous leukemia in chronic phase. The low bioavailability of Dasatinib may be due to both incomplete oral absorption and first-pass metabolism. A prodrug, JLTN, was synthesized to minimize the first-pass effect of Dasatinib and improve the oral bioavailability following oral administration via targeting intestinal peptide transporter and enhancing chemical stability. Biological evaluation data indicated that there was a 150%-fold increase in oral bioavailability of this prodrug compared to the parent drug Dasatinib in monkeys.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Dasatinib
  • Humans
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / drug therapy
  • Macaca mulatta
  • Male
  • Prodrugs / chemical synthesis*
  • Prodrugs / pharmacokinetics*
  • Protein Kinase Inhibitors / chemical synthesis
  • Protein Kinase Inhibitors / pharmacokinetics
  • Pyrimidines / chemical synthesis*
  • Pyrimidines / pharmacokinetics*
  • Thiazoles / chemical synthesis*
  • Thiazoles / pharmacokinetics*

Substances

  • N-(2-chloro-6-methylphenyl)-2-((6-(4-(2-hydroxyethyl)piperazin-1-yl)-2-methylpyrimidin-4-yl)amino)-1,3-thiazole-5-carboxamide
  • Prodrugs
  • Protein Kinase Inhibitors
  • Pyrimidines
  • Thiazoles
  • Dasatinib