title: Deuterated clopidogrel analogues as a new generation of antiplatelet agents.
abstract: 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.
authors.affiliation: MetabQuest Research Laboratory , 202 Chengfu Road, Beijing 100871, People's Republic of China.
authors.forename: Yaoqiu
authors.initials: Y
authors.lastname: Zhu
authors.affiliation: Analytical Instrumentation Center, College of Chemistry and Molecular Engineering, Peking University , Beijing 100871, People's Republic of China.
authors.forename: Jiang
authors.initials: J
authors.lastname: Zhou
authors.affiliation: Department of Pharmacology, School of Pharmacy, Shandong University , Jinan, Shandong 250012, People's Republic of China.
authors.forename: Bo
authors.initials: B
authors.lastname: Jiao
keywords: Clopidogrel resistance; bioactivation potentiation; clinical variability; piperidine deuteration; prodrug attrition; targeted metabolic shift