Novel cilengitide-based cyclic RGD peptides as αvβ₃ integrin inhibitors

In this letter, we report a series of five new RGD-containing cyclic peptides as potent inhibitors to αvβ₃ integrin protein. We have incorporated various unnatural lipophilic amino acids into the cyclic RGD framework of cilengitide, which is selective for αvβ₃ integrin. All the newly synthesized cyclic peptides were evaluated in vitrosolid phase binding assay and investigated for their bindingbehaviourtowards integrin subtypes. All the cyclic peptides were synthesized in excellent yield following solution-phase coupling strategy. The cyclic RGD peptides 1a-e exhibited IC₅₀ of 9.9, 5.5, 72, 11 and 3.3 nM, respectively, towardsαvβ₃ integrin protein. This finding offers further opportunities for the introduction unusual amino acids into the cyclic peptide framework of cilengitide.