Tricyclic pharmacophore-based molecules as novel integrin αvβ3 antagonists. Part IV: Preliminary control of αvβ3 selectivity by meta-oriented substitution

To establish the in vivo efficacy of αvβ3/αIIbβ3 dual antagonists possessing a tricyclic pharmacophore, a corresponding αvβ3-selective antagonist was required as a control. We initially took two synthetic approaches to obtain αvβ3-selective antagonists based on the RGD recognition pattern or on modification of the dihedral angle between the central benzene ring and the adjacent heterocycle, but both proved unsuccessful. However, synthesis of novel antagonists with meta-substitution of the central benzene ring generated weak selectivity for αvβ3 over αIIbβ3 for the first time in the family of compounds with the tricyclic pharmacophore. Optimization of meta-oriented antagonists furnished an αvβ3-selective antagonist exhibiting inhibitory activity not only in a receptor-binding assay, but also in a cell adhesion assay.

We found an αvβ3 selective antagonist to demonstrate the in vivo efficacy of αvβ3/αIIbβ3 dual antagonists processing a tricyclic pharmacephore.Figure optionsDownload as PowerPoint slide