Ticagrelor-Acute myocardial infarction

Ticagrelor is a new type of oral antiplatelet drug of cyclopentyltriazole pyrimidine. It was launched in Europe in December 2010. It has been approved for marketing in 85 countries including the United States. It is used for the treatment of ACS. The active drug, by directly and reversibly binding to the P2Y12 receptor at the ADP binding site, effectively inhibits ADP-mediated activation of the P2Y12 receptor. The receptor will still function after ticagrelor is detached, and ADP can still bind to the original binding site. Binding; At the same time, the active metabolite AR-C124910XX of ticagrelor (metabolized by the CYP3A pathway) can also antagonize the P2Y12 receptor, thereby enhancing the antiplatelet function.

Indications

This product is used for patients with acute coronary syndrome (unstable angina pectoris, non-ST-segment elevation myocardial infarction or ST-segment elevation myocardial infarction), including patients receiving drug therapy and percutaneous coronary intervention (PCI) treatment, reducing The incidence of thrombotic cardiovascular events.

Pharmacological action

Ticagrelor is a cyclopentatriazole pyrimidine (CPTP) compound. Ticagrelor and its main metabolites can reversibly interact with platelet P2Y12ADP receptors to block signal transduction and platelet activation, which is equivalent to the activity of its active metabolites.

Ticagrelor does not require liver drug enzyme metabolic activation and can quickly and reversibly antagonize P2Y12 receptors, thereby avoiding individual differences in drug efficacy due to differences in metabolic enzyme activity during metabolic activation. Therefore, patients who are resistant to clopidogrel benefit More.

Because ticagrelor is mainly cleared by the liver, and its safety has not been evaluated in patients with severe liver damage, it is contraindicated in such patients; in addition, ticagrelor is metabolized by CYP3A4, so it is not recommended to interact with CYP3A4 strong inhibitors or The inducer is used in combination. The pharmacokinetic parameters and pharmacodynamics of ticagrelor are not affected by whether clopidogrel is taken before treatment or the hyporesponsiveness to clopidogrel, which indicates that patients can directly replace clopidogrel with ticagrel if necessary The pharmacodynamic data shows that compared with clopidogrel, ticagrelor can quickly and continuously produce a dose-dependent platelet inhibitory effect, significantly reducing ACS patients, including cardiovascular death, myocardial infarction and stroke. The primary composite end point of the drug does not significantly increase the risk of major bleeding, and its effect is not affected by the genotypes of CYP2C19 and ABCB1. Therefore, the new antiplatelet drug ticagrelor is expected to make use of its unique pharmacokinetic and pharmacodynamic characteristics. More ACS patients benefit.

Synthesis Method

Synthesized from 5-(2-hydroxyethoxy)cyclopentane-1,2-diol intermediate and (S)-2-(tert-butoxycarboxamido)propionic acid as raw material, after 10 steps of reaction ; Intermediate 4,6-dichloro-5-nitro-2-propylthiopyrimidine takes 5-nitro-2-propylthiopyrimidine-4,6-diol as a raw material through 3-step synthesis; The above two intermediates were synthesized in 3 steps to obtain 5-propylthio-3hydro-[1,2,3]triazole[4,5-d]pyrimidin-3-yl)-5-(2-hydroxyethoxy Base) cyclopentane-1,2-diol; another important intermediate 2-(3,4-difluorophenyl) cyclopropylamine is (E)-3-(3,4-difluorobenzene Acrylic acid is used as a raw material and synthesized through a 5-step reaction. Finally, the two fragments are connected to obtain the target compound ticagrelor. The specific reaction process is as follows: