Design,Synthesis And Biological Activity Study Of Adenosine Derivatives As P2Y12 Inhibitors

Atherosclerosis is the most common pathological basis of coronary artery diseases,peripheral artery diseases and cerebrovascular diseases.With long-term development,it can lead to the formation of arterial thrombosis and eventually lead to myocardial infarction,cerebral infarction and other cardiovascular and cerebrovascular diseases.Atherosclerosis is a symptom of lipid metabolism disorder.It can lead to the formation of the plaque which can change the flow velocity of the blood in the blood vessel.It can increase the pressure produced by the blood flow on the blood vessel endothelium.Finally,the plaque ruptures and makes the blood vessel endothelium injured.It will activate platelets and make them gather at the injury site to form thrombosis which is harmful to human health.There are many receptors on the surface of platelets,and P2Y12 receptor is an important participant in platelet activation and aggregation to form thrombus.During the activation of platelets,activated platelets release adenosine diphosphate（ADP）,which is an endogenous agonist to the P2Y12 receptors.And it can make P2Y12 receptors activate which will cause platelets to aggregate.At the same time,the activation of P2Y12 receptor can also help to product a variety of platelet activating substances which can promote platelets aggregation.Therefore,it can achieve the effect of anti-platelet aggregation by inhibiting the functions of P2Y12 receptors.So,it is practically significant to develop P2Y12 inhibitors.In this paper,P2Y12 receptor was chosen as the target.Based on the listed drugs including Ticagrelor and Cangrelor,and the existing structure-activity relationship which has been summarized from previous work,the adenosine was designed as main structure of the core structure.Development experience of some drugs and some natural products which contain glucoside structure were used for reference to modify the core structure.Therefore,22 new compounds were designed and synthesized which have never been reported before.It is the innovation of this paper.Their structures were determined by ¹H-NMR,¹³C-NMR and mass spectrometry.And their biological activity aimed at P2Y12 receptor was tested by LANCE-Ultra-c AMP method.Compound 23 shows the best activity which IC₅₀value is 0.49μM.Compounds 14,22 and 53 show good activity which IC₅₀values are respectively 4.46μM,2.62μM and 2.47μM.In addition,compounds 32,40,41,59 and 60 also show some activity,which IC₅₀values are respectively 46.63μM,65.61μM,14.90μM,53.61μM and 11.89μM.Structure-activity relationship can be summarized by comparing and analyzing the structures of the synthesized compounds.When the 6 substituent group of adenine in the core structure（R group）is（1R,2S）-2-（3,4-difluorophenyl）cyclopropyl group,the molecules can obtain the best activity.It often leads to the activity reduction or disappearance when making changes on this group.When the glycoside in the core structure isβ-D-ribofuranose,the molecules can obtain the best activity.Compared with the molecules containβ-L-ribofuranose which has chiral changed hydroxyl groups in the core structure,the activity of the molecules containβ-D-ribofuranose is about 100 times higher than the latter.Compared with the molecules containβ-D-galactose which has larger ring structure in the core structure,the activity of the molecules containedβ-D-ribofuranose is about 30 times higher than the latter.Compared with the molecules contain 3-deoxy-D-ribose which loses the 3’-hydroxy group in the core structure,the activity of the molecules containβ-D-ribofuranose is about 5 times higher than the latter.When the 2 substituent group of adenine in the core structure is propyl thionyl group,the molecules can obtain the best activity.Compared with the molecules use propyl sulfonyl group which is oxidized from propyl thionyl group as the 2 substituent group,the activity of the molecules contain propyl thionyl group is about 25 times higher than the latter.The core structure designed and the series of compounds synthesized in this paper can be used to summary the structure-activity relationship.Compound 23 shows the best activity which IC₅₀value is 0.49μM,it can provide reference for further optimization of such drugs in the future.