Design and synthesis of a new class of selective integrin α5β1 antagonists

Starting from the structure of integrin alpha v beta 3 in a complex with a peptidic ligand plus SAR data on nonpeptidic ligands, we derived a new class of integrin alpha 5 beta 1 antagonists (1). Several synthesis strategies were applied to evaluate the chemical space around the essential pharmacophore groups R-1 to R-3 to obtain highly active and selective pyrrolidine derivatives as integrin alpha 5 beta 1 antagonists. Integrin selectivity was controlled by switching from a sulfonamide moiety to a mesitylene amide moiety for R3. This finding represents a general feature for modulating selectivity toward other related integrin receptors. On the basis of the encouraging results from various in vitro studies, the most active compounds were selected for further in vivo studies in animal models and preclinical development.