The Design of Potent, Selective and Drug-Like RGD αvß1 Small-Molecule Inhibitors Derived from non-RGD α4ß1 Antagonists.

Up to 45 % of deaths in developed nations can be attributed to chronic fibroproliferative diseases, highlighting the need for effective therapies. The RGD (Arg-Gly-Asp) integrin αvß1 was recently investigated for its role in fibrotic disease, and thus warrants therapeutic targeting. Herein we describe the identification of non-RGD hit small-molecule αvß1 inhibitors. We show that αvß1 activity is embedded in a range of published α4ß1 (VLA-4) ligands; we also demonstrate how a non-RGD integrin inhibitor (of α4ß1 in this case) was converted into a potent non-zwitterionic RGD integrin inhibitor (of αvß1 in this case). We designed urea ligands with excellent selectivity over α4ß1 and the other αv integrins (αvß3, αvß5, αvß6, αvß8). In silico docking models and density functional theory (DFT) calculations aided the discovery of the lead urea series.