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.
Highlights
Clopidogrel (1) is a thienopyridine antiplatelet agent approved by the US Food and DrugAdministration (FDA) for the treatment of cardiovascular diseases, including atherothrombosis, unstable angina and myocardial infarction [1]
2-oxoclopidogrel exclusively place of the methyl ester in clopidogrel and, neither it nor its intermediate is of esterase-mediated hydrolysis (Scheme 2) [12]
SD-809, an analog of a superior pharmacokinetic profile which has led to a New Drug Application (NDA) for SD-809 to the tetrabenazine with deuterated methoxy groups, forms an active metabolite that undergoes CYP2D6FDA mediated for the treatment of chorea associated with Huntington’s disease
Summary
Clopidogrel (1) is a thienopyridine antiplatelet agent approved by the US Food and Drug. 2-oxoclopidogrel exclusively place of the methyl ester in clopidogrel and, neither it nor its intermediate is of esterase-mediated hydrolysis (Scheme 2) [12]. Such deuteration causes minimal structural perturbation and has little effect on the pharmacological activity of physiologically-active compounds [17] It can affect the rate of metabolism of drugs that undergo metabolism involving C–H bond scission, the effect is highly unpredictable and dependent on the specific compound and its deuterium substitution pattern. SD-809, an analog of a superior pharmacokinetic profile which has led to a New Drug Application (NDA) for SD-809 to the tetrabenazine with deuterated methoxy groups, forms an active metabolite that undergoes CYP2D6FDA mediated for the treatment of chorea associated with Huntington’s disease.
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