Design, synthesis and biological evaluation of deuterated Tivozanib for improving pharmacokinetic properties. Issue 11 (1st June 2015)

• Record Type: Journal Article
• Authors: Guo, Shiwei; Pang, Xuehai; Peng, Lingling; Zhan, Miao; Fan, Lei; Gong, Yu; Kang, Fanyuan; Chen, Yuanwei
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 25:Issue 11(2015)
• Page Start: 2425
• Page End: 2428
• Publication Date: 2015-06-01
• Subjects: Tivozanib -- Pharmacokinetics -- Deuterium isotopic effect -- Deuterated drug; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2015.03.088
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: 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 ( t 1/2 ) and increased AUC0–∞ . Therefore, HC-1144 has the potential to be a novel inhibitor against VEGFR tyrosine kinases with long-acting plasma exposure.