The Design of Potent, Selective and Drug-Like RGD αvβ1 Small-Molecule Inhibitors Derived from non-RGD α4β1 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 αvβ1 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 αvβ1 inhibitors. We show that αvβ1 activity is embedded in a range of published α4β1 (VLA-4) ligands; we also demonstrate how a non-RGD integrin inhibitor (of α4β1 in this case) was converted into a potent non-zwitterionic RGD integrin inhibitor (of αvβ1 in this case). We designed urea ligands with excellent selectivity over α4β1 and the other αv integrins (αvβ3, αvβ5, αvβ6, αvβ8). In silico docking models and density functional theory (DFT) calculations aided the discovery of the lead urea series.