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

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 ( t(1/2)) and increased AUC(0-infinity). Therefore, HC-1144 has the potential to be a novel inhibitor against VEGFR tyrosine kinases with long-acting plasma exposure. (C) 2015 Elsevier Ltd. All rights reserved.