Xie_2025_Biochem.Pharmacol__117330

Clopidogrel is one of the World Health Organization-recommended essential medicines used for antiplatelet therapy. However, its usage is limited by resistance of patients to clopidogrel. Herein, we systematically summarized promising novel analogs of clopidogrel and evaluated their preclinical and clinical properties as well as the science behind the study. The primary strategy of their design and synthesis is largely focused on how to enhance their metabolic activation, significantly increasing the systemic exposure of their active thiol metabolites (such as H4). Of these, DT-678 released H4 into the blood following exposure to GSH due to bypassing all cytochrome P450-mediated metabolic activation processes of clopidogrel; evategrel (formerly CG-0255) was converted to H4 by esterase-catalyzed hydrolysis. Vicagrel, acetate of clopidogrel, was completely hydrolyzed to 2-oxo-clopidogrel by intestinal hydrolases, thus bypassing the first-step oxidation of clopidogrel and consequently increasing the formation of H4. The same strategies as those for prasugrel and vicagrel were used to design new compounds, such as tipidogrel, compound 6b, PLD-301, and W-1. In addition, 2-oxo-clopidpgrel, an intermediate metabolite shared by clopidogrel, vicagrel, PLD-301, and W-1, was used to determine whether it could exert the same antiplatelet effect as its parent drugs. Moreover, clopidogrel and vicagrel were also deuterated to further increase the formation of H4 in the liver. All these new compounds in the pipeline are promising antiplatelet drugs, and superior to clopidogrel. DT-678 and evategrel are considered the best clopidogrel analogs that may overcome clopidogrel resistance due to their superior efficacy and safety profiles over clopidogrel.