Design, Synthesis and Pharmacokinetic Study of Deuterated Ticagrelor Derivatives

Abstract Ticagrelor is the first reversible P2Y 12 receptor antagonist that inhibits ADP‐induced platelet aggregation. In several areas of biomedical research, the deuterium strategy has been employed to slow down the rate of drug metabolism and improve the pharmacokinetic properties of drugs. In the present study, several deuterated analogs of ticagrelor, as well as their prodrugs, were designed and synthesized in order to improve the metabolic stability of ticagrelor. Further in vitro and in vivo pharmacokinetic experiments using the deuterated derivates 24 and 25 demonstrated that the metabolic stability of deuterated compounds was improved compared to that of the parent compound. In addition, the half‐life of the deuterated valine ester prodrug 31 (t 1/2 =2.54±0.32 h) was significantly lengthened, reaching a value of approximately 40 % longer than that of ticagrelor (t 1/2 =1.77±0.14 h).