title: Significant Improvement of Metabolic Characteristics and Bioactivities of Clopidogrel and Analogs by Selective Deuteration.
abstract: In the search for prodrug analogs of clopidogrel with improved metabolic characteristics and antiplatelet bioactivity, a group of clopidogrel and vicagrel analogs selectively deuterated at the benzylic methyl ester group were synthesized, characterized, and evaluated. The compounds included clopidogrel-d₃ (8), 2-oxoclopidogrel-d₃ (9), vicagrel-d₃ (10a), and 12 vicagrel-d₃ analogs (10b-10m) with different alkyl groups in the thiophene ester moiety. The D₃C-O bond length in 10a was shown by X-ray single crystal diffraction to be shorter than the H₃C-O bond length in clopidogrel, consistent with the slower rate of hydrolysis of 8 than of clopidogrel in rat whole blood in vitro. A study of the ability of the compounds to inhibit ADP-induced platelet aggregation in fresh rat whole blood collected 2 h after oral dosing of rats with the compounds (7.8 μmol/kg) showed that deuteration increased the activity of clopidogrel and that increasing the size of the alkyl group in the thiophene ester moiety reduced activity. A preliminary pharmacokinetic study comparing 10a with vicagrel administered simultaneously as single oral doses (72 μmol/kg of each drug) to male Wistar rats showed 10a generated more of its active metabolite than vicagrel. These results suggest that 10a is a potentially superior antiplatelet agent with improved metabolic characteristics and bioactivity, and less dose-related toxicity.
authors.affiliation: College of Life Sciences, Jilin University, Qianjin Street, Changchun 130012, China. x-album@163.com.
authors.forename: Xueyu
authors.initials: X
authors.lastname: Xu
authors.affiliation: College of Life Sciences, Jilin University, Qianjin Street, Changchun 130012, China. zhaoxue1310@163.com.
authors.forename: Xue
authors.initials: X
authors.lastname: Zhao
authors.affiliation: College of Life Sciences, Jilin University, Qianjin Street, Changchun 130012, China. yangzhichao3639@163.com.
authors.forename: Zhichao
authors.initials: Z
authors.lastname: Yang
authors.affiliation: College of Life Sciences, Jilin University, Qianjin Street, Changchun 130012, China. wanghao340702@126.com.
authors.forename: Hao
authors.initials: H
authors.lastname: Wang
authors.affiliation: Research Center for Drug Metabolism, Jilin University, Qianjin Street, Changchun 130012, China. mengxj1990@163.com.
authors.forename: Xiangjun
authors.initials: X
authors.lastname: Meng
authors.affiliation: Research Center for Drug Metabolism, Jilin University, Qianjin Street, Changchun 130012, China. suchonghappy1@sina.com.
authors.forename: Chong
authors.initials: C
authors.lastname: Su
authors.affiliation: Department of Pharmacology, School of Basic Medical Sciences, Jiamusi University, Jiamusi 154007, China. liumingyuan12@163.com.
authors.forename: Mingyuan
authors.initials: M
authors.lastname: Liu
authors.affiliation: School of Pharmacy, University of Otago, P.O. Box 56, Dunedin, New Zealand. paul.fawcett@otago.ac.nz.
authors.forename: John Paul
authors.initials: JP
authors.lastname: Fawcett
authors.affiliation: Research Center for Drug Metabolism, Jilin University, Qianjin Street, Changchun 130012, China. yyan@jlu.edu.cn.
authors.forename: Yan
authors.initials: Y
authors.lastname: Yang
authors.affiliation: College of Life Sciences, Jilin University, Qianjin Street, Changchun 130012, China. gujk@jlu.edu.cn.|Clinical Pharmacology Center, Research Institute of Translational Medicine, The First Hospital of Jilin University, Dongminzhu Street, Changchun 130061, China. gujk@jlu.edu.cn.
authors.forename: Jingkai
authors.initials: J
authors.lastname: Gu
mesh_terms: D000244:Adenosine Diphosphate / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D000077144:Clopidogrel; D006868:Hydrolysis; D008297:Male; D053858:Metabolic Networks and Pathways; D008958:Models, Molecular; D008968:Molecular Conformation; D010648:Phenylacetates / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism* / Q000493:pharmacokinetics*; D051381:Rats; D013876:Thiophenes / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D013988:Ticlopidine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics
chemical_list: D010648:Phenylacetates; D010975:Platelet Aggregation Inhibitors; D013876:Thiophenes; C574646:methyl 2-(2-acetoxy-6,7-dihydrothieno(3,2-c)pyridin-5(4H)-yl)-2-(2-chlorophenyl)acetate; D000244:Adenosine Diphosphate; D000077144:Clopidogrel; D013988:Ticlopidine
keywords: active metabolite; antiplatelet agent; clopidogrel; deuteration; prodrug; vicagrel