Compound 58l is a novel oral P2Y12 antagonist that demonstrates potent antithrombotic efficacy and an improved safety profile compared to clopidogrel in preclinical models.
These derivatives support lead optimization for P2Y12 antagonism; leaves open clinical translation in cardiovascular disease.
antagonist AZD1283, a series of novel bicyclic pyridine derivatives were designed and synthesized. The cyclization of the ester substituent on the pyridine ring to the ortho-methyl group led to lactone analogues of AZD1283 that showed significantly enhanced metabolic stability in subsequent structure-pharmacokinetic relationship studies. The metabolic stability was further enhanced by adding a 4-methyl substituent to the piperidinyl moiety. Compound 58l displayed potent inhibition of platelet aggregation in vitro as well as antithrombotic efficacy in a rat ferric chloride model. Moreover, 58l showed a safety profile that was superior to what was observed for clopidogrel in a rat tail-bleeding model. These results support the further evaluation of compound 58l as a promising drug candidate.
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Kong et al. (2019) studied Thrombosis. Compound 58l vs. Clopidogrel was evaluated on Platelet aggregation, antithrombotic efficacy, and bleeding safety.
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