Discovery of a novel and potent antiplatelet thiol prodrug CG-0255

A series of novel thiol prodrugs based on clopidogrel active metabolite H4 were conceived and synthesized as a new generation of antiplatelet agents. The prodrugs are capable of being rapidly converted to H4 through fast one-step hydrolysis catalyzed by carboxylesterases, thus potentially overcoming clopidogrel resistance and many other issues caused by the reliance of clopidogrel on cytochrome P-450 (CYP)-mediated oxidative bioactivation. One of the thiol prodrugs, CG-0255, was selected for further development. CG-0255 exhibited excellent pharmacokinetic and pharmacodynamic properties suitable for being developed as a once daily oral antiplatelet drug. In addition, CG-0255 possessed adequate solubility and chemical stability capable of being formulated as an intravenous formulation, expanding its uses into surgical or emergency settings where intravenous administration is more desired. CG-0255 is the first P2Y₁₂ inhibitor available in both intravenous and oral formulation, showing several advantages, such as rapid onset of action, low risk of drug-drug interaction, and an expected reduction in individual variation.