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.

中文翻译：

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具有克服氯吡格雷耐药性潜力的强效口服生物可利用抗血小板剂 PLD-301

PLD-301 是 Prelude Pharmaceuticals 发现的氯吡格雷硫内酯磷酸盐前药，旨在克服氯吡格雷耐药性，评估了其对 ADP 诱导的大鼠血小板聚集的体内抑制作用。PLD-301 的效力与普拉格雷相似，但远高于氯吡格雷。药代动力学分析结果表明，PLD-301转化的氯吡格雷硫内酯的口服生物利用度比氯吡格雷转化的高4-5倍，表明与氯吡格雷相比，较低剂量的PLD-301可临床上使用。总之，PLD-301 是一种有效的、口服生物可利用的抗血小板药物，可能比氯吡格雷具有一些优势，例如克服 CYP2C19 等位基因功能丧失载体的氯吡格雷耐药性，