Evaluation of efficacy and safety after replacement of methyl hydrogen
with Deuterium at 7-position methyl formate of Clopidogrel
Abstract
Background and Purpose: As a first-line clinical drug, thienopyridines
still have many unsatisfactory aspects, such as the low bioavailability
of clopidogrel and the high bleeding risk of prasugrel. Our team
synthesized deuterium clopidogrel(the patent has been obtained in China)
to mitigate the disadvantages of clopidogrel clinical application,
including a slow onset, greater influence of gene polymorphism and
drug-drug interaction. Experimental Approach: Molecular docking
technology was used to analyze the affinity between deuterium
clopidogrel and P2Y12 receptor; The levels of active metabolites of
deuterium clopidogrel in vivo were detected by HPLC/MS-MS and the
activities of main metabolic enzymes was analyzed; Subsequently,
platelet aggregation function, thrombus model were used to evaluate the
pharmacodynamics of deuterium clopidogrel; Finally, the safety of
deuterium clopidogrel were evaluated by blood routine, PT, APTT,
bleeding time, serological tests, liver pathological biopsy, liver cell
apoptosis and apoptosis-related protein detection. Key Results: The
introduction of deuterium makes the binding of clopidogrel to P2Y12
receptor more stable, improves the concentration of active metabolites,
reduces the inhibition of major metabolic enzymes including CYP2B6,
CYP2C9 and CYP2C19, leading to the better anti-platelet effect without
increasing the risk of bleeding, and leads to the decrease in the degree
of hepatocyte apoptosis. Conclusion and Implications: In terms of both
efficacy and safety, deuterium clopidogrel has a better effect, the
present findings render deuterium clopidogrel a promising candidate for
clinical application in thromboembolism disease and provides a new idea
for the development of this new antithrombotic drug.