Design, synthesis and biological evaluation of deuterated Tivozanib for improving pharmacokinetic properties

Bioorg Med Chem Lett. 2015 Jun 1;25(11):2425-8. doi: 10.1016/j.bmcl.2015.03.088. Epub 2015 Apr 4.

Abstract

Tivozanib is a potent and selective tyrosine kinase inhibitor of vascular endothelial growth factor receptor-1(VEGFR1), -2(VEGFR2), and -3(VEGFR3). Analog of Tivozanib with deuterium-for-hydrogen replacement in metabolically active site was prepared and evaluated in vitro. Compared to its prototype, deuterated Tivozanib compound HC-1144 retained in vitro activity against VEGFR tyrosine kinases. In vivo pharmacokinetic studies indicated HC-1144 clearly altered the blood circulation behavior, which was proved by significantly prolonged blood circulation half life time (t1/2) and increased AUC0-∞. Therefore, HC-1144 has the potential to be a novel inhibitor against VEGFR tyrosine kinases with long-acting plasma exposure.

Keywords: Deuterated drug; Deuterium isotopic effect; Pharmacokinetics; Tivozanib.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Area Under Curve
  • Deuterium*
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / pharmacokinetics
  • Half-Life
  • Male
  • Phenylurea Compounds / chemical synthesis
  • Phenylurea Compounds / chemistry*
  • Phenylurea Compounds / pharmacokinetics*
  • Quinolines / chemical synthesis
  • Quinolines / chemistry*
  • Quinolines / pharmacokinetics*
  • Rats
  • Rats, Sprague-Dawley

Substances

  • Enzyme Inhibitors
  • Phenylurea Compounds
  • Quinolines
  • tivozanib
  • Deuterium