The platelet aggregation is a crucial step in a pathophisiology of thromboses, leading to development of cardio-vascular diseases (myocardial infarction, transient ischemic attacks, strokes, etc.). The final step in the aggregation is the binding of fibrinogen to receptor - glycoprotein IIb/IIIa (GP IIb/IIIa) on the surface of activated platelets. In recent years the increasing attention is paid to the role of fibrinogen antagonists in the prevention of thrombosis. The search for these compounds is based on the molecular design of structures mimicking some fragment of RGD (Arg-Gly-Asp) sequence, responsible for the binding of fibrinogen to GP IIb/IIIa. Up to now, a large number of potent and selective GP IIb/IIIa antagonists, including non-peptide inhibitors are identified (derivatives of benzodiazepines, aminobenzamidinosuccinyles, isoxazolines, isoquinolines). The modification of natural peptide structures for obtaining of more active and selective fibrinogen receptor antagonists is realized in several ways: substitution of main pharmacophores of RGD sequence; cyclization of RGD-containing peptides; design of conformationally constrained peptidomimetics. For the treatment of chronic cardio-vascular diseases, the clinic needs high orally active RGD-peptidomimetics. This task is realized by obtaining of prodrugs on the base of the most potent RGD-mimetics. In our laboratory the molecular design and synthesis of non-peptide fibrinogen receptor antagonists were carried out. The series of RGD-mimetics on the basis of 4-oxo-(piperazine-1-yl)butyric acid as Arg-mimetic and beta-aryl-beta-alanines as Asp-Phe-mimetics were synthesized. Obtained RGD-mimetics showed a high antiaggregatory activity in vitro experiments with IC(50)values of 10(-7) - 10(-9) M.

This article describes design, virtual screening, synthesis, and biological tests of novel αIIbβ3 antagonists, which inhibit platelet aggregation. Two types of αIIbβ3 antagonists were developed: those binding either closed or open form of the protein. At the first step, available experimental data were used to build QSAR models and ligand- and structure-based pharmacophore models and to select the most appropriate tool for ligand-to-protein docking. Virtual screening of publicly available databases (BioinfoDB, ZINC, Enamine data sets) with developed models resulted in no hits. Therefore, small focused libraries for two types of ligands were prepared on the basis of pharmacophore models. Their screening resulted in four potential ligands for open form of αIIbβ3 and four ligands for its closed form followed by their synthesis and in vitro tests. Experimental measurements of affinity for αIIbβ3 and ability to inhibit ADP-induced platelet aggregation (IC50) showed that two designed ligands for the open form 4c and 4d (IC50 = 6.2 nM and 25 nM, respectively) and one for the closed form 12b (IC50 = 11 nM) were more potent than commercial antithrombotic Tirofiban (IC50 = 32 nM).

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A series of novel RGD mimetics containing phthalimidine fragment was designed and synthesized. Their antiaggregative activity determined by Born's method was shown to be due to inhibition of fibrinogen binding to αIIbβ₃. Molecular docking of RGD mimetics to αIIbβ₃ receptor showed the key interactions in this complex, and also some correlations have been observed between values of biological activity and docking scores. The single crystal X-ray data were obtained for five mimetics.