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Molecules 2016, 21(6), 704; doi:10.3390/molecules21060704

Significant Improvement of Metabolic Characteristics and Bioactivities of Clopidogrel and Analogs by Selective Deuteration

College of Life Sciences, Jilin University, Qianjin Street, Changchun 130012, China
Research Center for Drug Metabolism, Jilin University, Qianjin Street, Changchun 130012, China
Department of Pharmacology, School of Basic Medical Sciences, Jiamusi University, Jiamusi 154007, China
School of Pharmacy, University of Otago, P.O. Box 56, Dunedin, New Zealand
Clinical Pharmacology Center, Research Institute of Translational Medicine, The First Hospital of Jilin University, Dongminzhu Street, Changchun 130061, China
Authors to whom correspondence should be addressed.
Academic Editors: Shufeng Zhou and Wei-Zhu Zhong
Received: 28 March 2016 / Revised: 19 May 2016 / Accepted: 25 May 2016 / Published: 30 May 2016
(This article belongs to the Special Issue Drug Design and Discovery: Principles and Applications)
View Full-Text   |   Download PDF [1184 KB, uploaded 30 May 2016]   |  


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 (10b10m) 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. View Full-Text
Keywords: deuteration; clopidogrel; vicagrel; prodrug; active metabolite; antiplatelet agent deuteration; clopidogrel; vicagrel; prodrug; active metabolite; antiplatelet agent

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Xu, X.; Zhao, X.; Yang, Z.; Wang, H.; Meng, X.; Su, C.; Liu, M.; Fawcett, J.P.; Yang, Y.; Gu, J. Significant Improvement of Metabolic Characteristics and Bioactivities of Clopidogrel and Analogs by Selective Deuteration. Molecules 2016, 21, 704.

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