Multicomponent Synthesis of Dihydropyridinone Containing Cyclic RGD Peptides
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چکیده
Inhibition of binding of extracellular matrix (ECM) proteins fibrinogen and vitronectin to the IIbβ3 and vβ3 integrins, respectively, is of great pharmaceutical interest. Both receptors recognize the RGD tripeptide sequence, which is present in these natural ligands. The development of antagonists for these integrins is therefore often based on this tripeptide unit and several cyclic RGD peptides have been developed as successful inhibitors. The incorporation of conformational constraints, like turn mimetics, in these cyclic peptides has proven to enhance their activity. In this chapter, the synthesis of two diastereomeric dihydropyridinone containing cyclic RGD peptides is reported, using our earlier developed MCR-Alkylation-MCR strategy. The conformations were evaluated by NMR analysis and one of them by X-ray diffraction. These studies conclude that both diastereomers show rather similar conformations, with an extended RGD motif, suggesting high activity and selectivity for the IIbβ3 integrin. Inhibition studies performed on the IIbβ3 and vβ3 integrins showed high activities in the nanomolar range (for both diastereomers). However, the selectivity between the two receptors needs to be improved. Our multicomponent modular approach provides excellent opportunities for further optimization.
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