Arg-Gly-Asp (RGD) mimics were synthesized and their anti-platelet activity was evaluated. A concise method was developed for the synthesis of the target compounds from dehydroepiandrosterone and WielandMiescher and Hajos-Parrish ketones, which are suitable for readily available platform. Among the synthesized compounds, the perhydronaphthalene framework with a 3-(4-piperidinyl)propoxyl structure 3e possessed the highest anti-aggregative activity. The IC 50 values of 3e were 0.91 mM (ADP initiation) and 0.54 mM (collagen initiation).Key words non-peptide Arg-Gly-Asp (RGD) mimic; antiplatelet agent; dehydroepiandrosterone; WielandMiescher ketone; Hajos-Parrish ketone Platelets play an important role in hemostasis; however, its aggregation triggers several serious diseases, including cardiovascular, cerebrovascular, and peripheral vascular diseases. Platelet aggregation process is occurred by the stimulation of various physiological activators such as ADP, collagen and thrombin.1,2) Finally the stimulation derives the structural transformation of glycoprotein IIb/IIIa (integrin αIIbβ3) on the platelet surface. The activated GPIIb/IIIa receptor interacts with fibrinogen to induce platelet aggregation. [3][4][5] The interaction between GPIIb/IIIa and fibrinogen is mediated by the Arg-Gly-Asp (RGD) sequence in fibrinogen.6-8) Additionally, the β-turn structure formed by the sequence enhances the interaction of each molecules.9,10) Therefore, RGD mimics are valuable platelet aggregation antagonists, and many compounds have been developed. [11][12][13][14] Among them, tirofiban (1) 15) and eptifibatide (2), 16) were launched for clinical use (Fig. 1). To develop a more efficient approach to RGD mimics, we assumed that the shape and volume of the β-turn structure is equal to that of perhydro polycyclic hydrocarbon structures such as perhydro-phenanthrene, 17,18) -naphthalene, and -indene (Fig. 2). Therefore, these hydrocarbons, with acidic and basic moieties of the appropriate position and size, were hypothesized to be good candidate for antiplatelet agents. Moreover, such compounds should be biologically stable and show better oral bioavailability than the peptide ligands. Additionally, a method for stereoselective transformation of such compounds is available, based on established concepts in steroid chemistry, enabling detailed conformational analysis of the ligand docking site. We planned to develop a method for synthesis of the orally active antiplatelet agents 3a-e from the readily available dehydroepiandrosterone (4) and Wieland-Miescher (5) and Hajos-Parrish ketones (6). Herein, we report the synthesis of the target peptide mimic compounds and an evaluation of those antiplatelet activities.
ChemistryFirst, for preparation of the perhydrophenanthrene compounds 3a and b, the common intermediate 11 was synthesized from dehydroepiandrosterone 4 (Chart 1). Acetalization of the ketone 4 19) and Oppenauer oxidation of the secondary alcohol accompanying isomerization of the olefin yielded an enone.20) The stereoselecti...
