Key result
Deuterated piperidine analogues of clopidogrel show greater prodrug activation and platelet inhibition than clopidogrel in rats.
Why the study?
Do deuterated clopidogrel analogues improve prodrug activation and antiplatelet activity compared to clopidogrel in preclinical models?
Do deuterated clopidogrel analogues improve prodrug activation and antiplatelet activity compared to clopidogrel in preclinical models?
Deuterated clopidogrel analogues show improved bioactivation and greater antiplatelet efficacy in preclinical models, offering a potential strategy to overcome clopidogrel resistance.
May warrant human pharmacokinetic studies; leaves open translation to clinical platelet inhibition.
Clopidogrel (CPG) is an antithrombotic prodrug that needs hepatic cytochrome P450 (CYP) enzymes for its bioactivation. The clinical effects of CPG have been associated with high intersubject variability and a certain level of resistance. Recently, comprehensive biotransformation studies of CPG support that the observed clinical uncertainty stems from the low bioactivation efficiency, which is attributed to extensive attritional metabolism (e.g., hydrolysis of the methyl ester functionality and oxidation of the piperidine moiety). With the goal of potentiating the desired thiophene 2-oxidation through minimal structural modification, we have adopted the strategy of targeted metabolism shift and have designed and synthesized deuterated piperidine analogues of CPG. In vitro studies showed that the prodrug activation percentages have been significantly increased for the deuterated analogues as a result of stability enhancement of the piperidine moiety. In a pharmacological study with a rat model, oral administration of the deuterated analogues also demonstrated higher inhibitory activity than that of CPG against adenosine diphosphate (ADP) induced platelet aggregation. These deuterated analogues represent a new generation of antiplatelet agents with the potential to overcome the major clinical drawbacks of CPG.
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Zhu et al. (2013) studied this question. Deuterated piperidine analogues of clopidogrel vs. Clopidogrel (CPG) was evaluated on Prodrug activation percentages (in vitro) and inhibitory activity against ADP-induced platelet aggregation (in vivo). Deuterated piperidine analogues of clopidogrel demonstrated increased prodrug activation in vitro and higher inhibitory activity against ADP-induced platelet aggregation in rats compared to clopidogrel.
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