title: Design, synthesis and biological evaluation of deuterated Tivozanib for improving pharmacokinetic properties.
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.
authors.affiliation: State Key Laboratory of Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu 610041, China.
authors.forename: Shiwei
authors.initials: S
authors.lastname: Guo
authors.affiliation: Chengdu Institute of Organic Chemistry, Chinese Academy of Sciences, Chengdu 610041, China.
authors.forename: Xuehai
authors.initials: X
authors.lastname: Pang
authors.affiliation: State Key Laboratory of Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu 610041, China.
authors.forename: Lingling
authors.initials: L
authors.lastname: Peng
authors.affiliation: State Key Laboratory of Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu 610041, China.
authors.forename: Miao
authors.initials: M
authors.lastname: Zhan
authors.affiliation: Hinova Pharmaceuticals Inc, Suite 801, Building C1, #88 South KeYuan Road, Chengdu Tianfu Life Science Park, Chengdu 610041, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Fan
authors.affiliation: Hinova Pharmaceuticals Inc, Suite 801, Building C1, #88 South KeYuan Road, Chengdu Tianfu Life Science Park, Chengdu 610041, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Gong
authors.affiliation: Chengdu Institute of Organic Chemistry, Chinese Academy of Sciences, Chengdu 610041, China.
authors.forename: Fanyuan
authors.initials: F
authors.lastname: Kang
authors.affiliation: State Key Laboratory of Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu 610041, China; Hinova Pharmaceuticals Inc, Suite 801, Building C1, #88 South KeYuan Road, Chengdu Tianfu Life Science Park, Chengdu 610041, China. Electronic address: ywchen@scu.edu.cn.
authors.forename: Yuanwei
authors.initials: Y
authors.lastname: Chen
mesh_terms: D000818:Animals; D019540:Area Under Curve; D003903:Deuterium; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000493:pharmacokinetics; D006207:Half-Life; D008297:Male; D010671:Phenylurea Compounds / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics*; D011804:Quinolines / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D004791:Enzyme Inhibitors; D010671:Phenylurea Compounds; D011804:Quinolines; C553176:tivozanib; D003903:Deuterium
keywords: Deuterated drug; Deuterium isotopic effect; Pharmacokinetics; Tivozanib