Design and synthesis of deuterium-labeled vorapaxar / 中国药科大学学报

Vorapaxar,a novel antagonist of the protease-activated receptor 1 (PAR-1 ),can inhibit the clotting process. Deuterium-labeled vorapaxar was required for the analysis of clinical sample as an internal stand-ard. Starting for unlabeled vorapaxar,four-step reactions including hydrolysis,condensation,transesterification and hydrogen-deuterium exchange were carried out to synthesize [D8]vorapaxar effectively for the first time. All intermediates and final products were confirmed by NMR and high resolution mass spectrometry (HRMS).Impor-tantly,the prepared [D8]vorapaxar could meet the requirements of sample analysis as the internal standard.

Vorapaxar, a novel oral antiplatelet drug.

Vorapaxor is first in the class of protease activated receptor 1 (PAR 1) antagonists. It acts by inhibiting the binding of thrombin to PAR 1 and thereby prevents platelet aggregation. USFDA approved it in May 2014 as the results of clinical trials showed that the benefit: risk ratio was high. It is to be used in a dose of 2.5 mg once daily as triple antiplatelet therapy with aspirin and clopidogrel for reduction of thrombotic cardiovascular events in patients with a history of myocardial infarction or peripheral arterial disease. Increase in the incidence of intracranial hemorrhage is the major side-effect seen.