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

Xueyu Xu; Xue Zhao; Zhichao Yang; Hao Wang; Xiangjun Meng; Chong Su; Mingyuan Liu; Fawcett, John Paul; Yan Yang; Jingkai Gu

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 (7.8μmol/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 (72μmol/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.

PRODRUGS; PLATELET aggregation inhibitors; CLOPIDOGREL; ALKYL group; PHARMACOKINETICS; THIOPHENE derivatives

Molecules, 2016, Vol 21, Issue 6, p704

1420-3049

Academic Journal

10.3390/molecules21060704