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Peptidomimetics - Antagonists of the Fibrinogen Receptors: Molecular Design, Structures, Properties and Therapeutic Applications

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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 RGDmimetics. 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 Argmimetic and β-aryl-β-alanines as Asp-Phe-mimetics were synthesized. Obtained RGD-mimetics showed a high antiaggregatory activity in vitro experiments with IC50 values of 10-7 - 10-9 M.

Keywords: affinity; antiaggregatory activity; fibrinogen receptor antagonists; prodrugs; rgd-peptidomimetics; thromboses

Document Type: Review Article


Affiliations: A.V. Bogatsky Physico- Chemical Institute of National Academy of Science of Ukraine, 86, Lustdorfskaya doroga, 65080 Odessa, Ukraine.

Publication date: 2004-05-01

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