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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

1
College of Life Sciences, Jilin University, Qianjin Street, Changchun 130012, China
2
Research Center for Drug Metabolism, Jilin University, Qianjin Street, Changchun 130012, China
3
Department of Pharmacology, School of Basic Medical Sciences, Jiamusi University, Jiamusi 154007, China
4
School of Pharmacy, University of Otago, P.O. Box 56, Dunedin, New Zealand
5
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)
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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 (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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MDPI and ACS Style

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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