Study On Antiplatelet Effect Of A New Thiophenopyridine P2Y₁₂ Receptor Antagonist DV-127

Thiophenopyridine P2Y₁₂ receptor antagonist is a hot topic in the field of antiplatelet research.Currently,the drugs mainly include the first generation of ticlopidine,the second generation of clopidogre,the combination of clopidogrel for antiplatelet aggregation in patients after PCI has been widely recommended in clinical guidelines.However,clopidogrel treatment still has many drawbacks,such as individual differences,some patients did not produce antiplatelet effect after treatment,that is“clopidogrel resistance”,and may increase the incidence of adverse reactions when combined with proton pump inhibitors,etc.The third generation of this class of drugs is prasugrel.Clinical application shows that prasugrel has a stronger inhibitory effect on platelet aggregation than clopidogrel.But the risk of prasugrel causing bleeding events is significantly higher.This topic uses clopidogrel as a basic model,utilizes the principle of deuteration,2-position group changing technology,the structure of this kind of compound is reconstructed,and a series of derivatives are obtained,in order to find a kind of drug which can bring the effect to the maximum and reduce the toxic side effect to the lowest.The results of previous pharmacokinetic studies showed that DV-127 has a good pharmacokinetic advantage.On this basis,we conducted in-depth research and discussion on the anti-platelet effect and potential hepatotoxicity of DV-127.The results are as follows:Part ?:Preliminary analysis of anticoagulant effect of DV-127.The experimental animals were Kunming mice,male and female,and were randomly divided into vehicle control group?0.5%CMC-Na?,DV-127 low dose group?0.4 mg/Kg?,DV-127medium dose group?0.8 mg/Kg?,DV-127 high dose group?1.6mg/Kg?,clopidogrel group?15mg/Kg?.The effect of DV-127 on coagulation time was determined by capillary tube method.The results showed that compared with the vehicle group?102.00±25.29s?,DV-127 medium and high dose group?201.00±42.54s,219.00±53.01s?,clopidogrel group?189.00±49.09s?significantly prolonged the clotting time?P?0.01?.The effect of DV-127 on bleeding time was determined by tail-tail method,The results showed that,compared with vehicle group?840.00±262.29s?,there was no significant difference between DV-127 low-and medium-dose groups?1095.00±335.93s,1164.00±282.06s??P?0.05?;DV-127 high dose group?1797.00±588.46s?and clopidogrel group?2259.00±746.60s?can significantly prolong the bleeding time?P?0.01?.DV-127 mid-dose group had a smaller effect on bleeding time than clopidogrel and had the advantage of reducing the risk of bleeding.Part ?:Effect of DV-127 on platelet function.Male Kunming mice,grouped as above;Male Wistar rats were randomly divided into vehicle control group?0.5%CMC-Na?,DV-127 low dose group?0.25 mg/Kg?,DV-127 medium dose group?0.5mg/Kg?,and DV-127 high dose group?1.0 mg/Kg?,clopidogrel group?10 mg/Kg?.The platelet adhesion function was measured by the glass ball method,the platelet aggregation function was determined by Born's turbidimetry,and the platelet particle release function?GMP-140??-TG?5-HT?ATP?was determined by ELISA.The experimental results showed that:1)Compared with vehicle group?0.1048±0.0343?,DV-127 low dose group?0.0799±0.0143,P?0.05?,DV-127 medium dose group?0.0727±0.0155,P?0.01?,DV-127 high dose group?0.0685±0.0210,P?0.01?,clopidogrel group?0.0651±0.0119,P?0.01?can significantly reduce platelet adhesion rate;2)compared with vehicle group?55.48±10.43%?,DV-127 middle dose group?42.43±14.42%,P?0.05?,DV-127 high dose group?39.55±12.44%,P?0.01?,clopidogrel group?43.04±9.94%,P?0.05?significantly reduced the maximum platelet aggregation rate within 5 min;3)Compared with vehicle group,DV-127 each dose group significantly inhibited the release of platelet particles?P?0.01?.Part ?:The effect of DV-127 on thrombosis.The experimental animals were grouped as above,and the rat in vitro thrombosis model was established:compared with vehicle group?6.969±2.227cm?,DV-127 medium dose group?4.719±1.379cm,P?0.01?,DV-127 high dose group?4.663±266cm,P?0.01?,clopidogrel group?4.313±1.137cm,P?0.01?can shorten the length of the thrombus,but also reduce the weight of the thrombus.Carrageenan induced thrombosis in mice,the results showed that compared with the vehicle group,DV-127 medium dose group?P?0.05?,DV-127 high dose group?P?0.01?,clopidogrel group?P?0.05?can significantly shorten the tail thrombus length in 24h,48h.Part ?:Preliminary analysis of DV-127 liver toxicity.The enzyme activities of alanine aminotransferase and aspartate aminotransferase were measured and histopathological sections were observed.The effect of DV-127 on liver toxicity was analyzed.The results of AST and ALT showed that there was no significant difference between the low,medium and high dose groups of DV-127 and clopidogrel group?P?0.05?.Histopathological sections of the liver showed that the DV-127 group and the clopidogrel group had no significant effect on liver tissue.Conclusion:DV-127 is a potential excellent antiplatelet drug,which can significantly shorten the bleeding time,reduce the platelet adhesion rate,effectively inhibit platelet aggregation and platelet particle release,and has significant antithrombotic effect,and has no effect on liver tissue.