Molecular Design,synthesis And Structure-activity Relationship Of Purine Nucleoside Derivatives As Reversible P2Y₁₂ Receptor Antagonists

The P2Y₁₂ receptor-mediated platelet aggregation process is very important for us to study thrombotic diseases.The P2Y₁₂ receptor antagonist has been widely studied as a new antiplatelet aggregation drug.Purine nucleoside derivative is a reversible P2Y₁₂ receptor antagonist with antithrombotic effect.The purine skeleton as the pharmacophore center of effect is the key to its biological activity.In this paper,36 purine derivatives and 39 adenosine derivatives were analyzed by three-dimensional quantitative structure-activity relationship（3D-QSAR）,including Co MFA,Co MSIA and SOMFA.A reliable calculation model was established and verified,which provides a basis for the molecular structure design of subsequent antiplatelet aggregation drugs.By exploring the changes of the types and numbers of molecules in the data set,it is found that expanding the molecular content of the data set is more beneficial to the significance and prediction ability of the model.By analyzing the 3D-QSAR calculation results,the following conclusions are drawn:the introduction of appropriate size groups at the C-2 position of purine ring is beneficial to the molecular activity,and the excessive group will inhibit the molecular activity;Large volume substituent groups cannot be directly connected at the C-6position of purine ring,and connecting groups with low electron cloud density will increase molecular activity.Connecting large volume groups at C-5’of sugar ring is beneficial to molecular activity,and hydrogen bond receptors in this region can also increase molecular activity.In this paper,the synthetic route of new purine nucleoside derivatives was also studied.The target products were synthesized successfully from2-amino-6-chloropurine andβ-D-furan ribose through four steps,and its structure was characterized.