Tricyclic pharmacophore-based molecules as novel integrin αvβ3 antagonists. Part 1: Design and synthesis of a lead compound exhibiting αvβ3/αIIbβ3 dual antagonistic activity

In order to generate novel compounds with integrin αvβ3-antagonistic activity together with antiplatelet activity, tricyclic pharmacophore-based molecules were designed and synthesized. Although piperazine-containing compounds initially prepared were selective αIIbβ3 antagonists, replacement of piperazine with piperidine furnished a potent αvβ3/αIIbβ3 dual antagonist. Structure–activity relationship (SAR) studies provided clues for further development of tricyclic pharmacophore-based integrin antagonists.

A linear and unfused-tricyclic pharmacophore, which was designed from an RGD tripeptide sequence, was synthesized as a novel non-peptide integrin αvβ3 antagonist.Figure optionsDownload as PowerPoint slide