Pharmacodynamics Research Of Anticlotting Innovation Drug QR02001

Rising living standards today,along with the aging intensifies,the incidence of th romboembolic disease is rising.Thrombosis causes stenosis and occlusion of lumen,and then make the major organs ischemic and infarcted to cause dysfunction.Therefor e,the number of deaths in China each year up to 2.6 million by it,so 12 million pe ople in the world,it has become public enemy number one of the human health.At present,the P2Y12-ADP receptor antagonist with its characteristics of both preve ntion and treatment effect of antiplatelet,it has become a major category of antithrombot ic drugs,aspirin and clopidogrel,is currently the standard combination of antiplatelet th erapy,has become the gold standard for the treatment of antithrombotic drugs.But the c ombination of the two drugs lead to increased risk of bleeding,and has been paid more and more attention of clopidogrel resistance and low bioavailability,the efficacy of anti platelet therapy is not good.In view of the above problems,to optimize the structure of clopidogrel,prasugre 1 and its metabolites and make out QR02 series compounds.This study used evaluation of rat plateletmaximum aggregation rate to define antiplatelet activity of QR02 series co mpounds,for better activity test,investigated the stability and toxicity of heart.Screened out candidate compounds QR02001 with a strong anti coagulant activity,good stabi lity and low cardiac toxicity.In this study,and then from three aspects of rat platelet aggregation rate,carragee nan induced mouse tail thrombosis model and rat arteriovenous shunt thrombosis model i nvestigatedcompound QR02001,were found in which is significantly superior to positiv e drug clopidogrel anticoagulation activity.At the same time in the rat tail bleeding tim e,compared with the positive drug clopidogrel,QR02001 compounds did not significantl y increase.Finally,the stability of QR02001 compound in the recombinant enzyme C YP2C19 and human plasma,good stability in the recombinant enzyme CYP2C19 showe d that it solves the problem of CYP2C19 metabolism,rapid hydrolysis in human plas ma by esterase shows prodrug design of QR02001 compound is correct,which may accel erate the onset time.Above all,anti coagulant activity of candidate compounds QR02001 from the select ion was significantly better than the positive drug clopidogrel,compared with the positiv e drug clopidogrel is not significantly increased at risk for bleeding,and solves the probl em of clopidogrel resistance.The results of this study achieved the screening expected,completed preliminary study of the pre clinical pharmacodynamics,provide the basis fo r the next comprehensive pre clinical development.