Antiplatelet 2-Hydroxy Thienopyridine Ester Derivatives for the Reduction of Thrombotic Cardiovascular Events

Introduction. Thienopyridine (TP) refers to the common structure – that is, 5-benzyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine – of a class of platelet aggregation inhibitors. Ticlopidine (2), clopidogrel (3), and the acetate ester of 2-hydroxy TP prasugrel (4, Figure 5.1) are the marketed drugs of the class. The TPs are bioprecursor prodrugs, which, after oral administration, undergo a cytochrome-mediated activation to active metabolites. Those in turn reduce or block in vivo platelet aggregation through irreversible inhibition of the purinergic receptor P2Y12 located on platelet cell membranes [1]. TPs are currently used to decrease the risk of thrombotic cardiovascular events related to the adenosine diphosphate (ADP)-induced platelet aggregation, occurring in several pathologies (e.g., cerebral ischemia, acute coronary syndrome (ACS), and arterial thrombosis) [2, 3]. After the discovery of ticlopidine (2), a number of analogs have been developed in order to improve efficacy and safety. An emerging favorable feature in antiplatelet TP analogs has been the acetate ester group in position 2 of the TP scaffold, which proved to significantly affect bioactivation and pharmacokinetics (PKs), ultimately making the newest TPs more efficacious and safer. This chapter focuses on the development of prasugrel (4), whose 2-OCOCH3 group plays an essential role in modulating the in vivo antiplatelet activity of TPs.