PLD-301, a phosphate prodrug of clopidogrel thiolactone discovered by Prelude Pharmaceuticals
with the aim to overcome clopidogrel resistance, was evaluated for its in vivo inhibitory effect
on ADP-induced platelet aggregation in rats. The potency of PLD-301 was similar to that of prasugrel,
but much higher than that of clopidogrel. The results of pharmacokinetic analysis showed that
the oral bioavailability of clopidogrel thiolactone converted from PLD-301 was 4- to 5-fold higher
than that of the one converted from clopidogrel, suggesting that in comparison with clopidogrel, lower
doses of PLD-301 could be used clinically. In summary, PLD-301 presents a potent and orally bioavailable antiplatelet
agent that might have some advantages over clopidogrel, such as overcoming clopidogrel resistance for CYP2C19-allele
loss-of-function carriers, and lowering dose-related toxicity due to a much lower effective dose.
Keywords: Clopidogrel, active metabolite, drug resistance, platelet ADP receptor, platelet aggregation, thrombosis.
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