Structure-activity relationship of RGD mimetics with 2H-1,4-benzoxazine-3(4H)-one scaffold

摘要

Platelet aggregation plays a vital role in primary haemostasis,but under pathological conditions,such as those following an atherosclerotic plaque rupture,this process may lead to an arterial thrombosis that can result in myocardial infarction,ischaemic stroke,and peripheral artery disease.The final common step in platelet aggregation is the binding of fibrinogen to its glycoprotein IIb/IIIa(GPIIb/IIIa,integrin alpha_(IIb)beta_3)receptor,which is located on the surface of activated platelets.Development of alpha_(IIb)beta_3 antagonists has been one of the main focuses in antithrombotic research over the last decade.They are based predominantly on the RGD(Arg-Gly-Asp)sequence found in many natural ligands of the receptor.According to the generally accepted model,a free carboxylic group and a basic functionality,in appropriate spatial positions,are the key pharmacophore elements of the GPIIb/IIIa antagonists,mimicking the aspartate beta-carboxylate and the arginine guanidinium group in the RGD sequence.In addition,an alkyl-or aryl-sulphonamide or carbamate functional group at the position a-to the carboxy terminus of the antagonist may constitute an additional,exosite-binding group.