Deuterated Clopidogrel
Analogues as a New Generation
of Antiplatelet Agents
- Publication date
- Publisher
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 <i>targeted metabolism shift</i> 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