Design and Synthesis of a New Class of Selective Integrin α5β1 Antagonists
journal contributionposted on 09.08.2007, 00:00 by Roland Stragies, Frank Osterkamp, Gunther Zischinsky, Doerte Vossmeyer, Holger Kalkhof, Ulf Reimer, Grit Zahn
Starting from the structure of integrin αvβ3 in a complex with a peptidic ligand plus SAR data on nonpeptidic ligands, we derived a new class of integrin α5β1 antagonists (1). Several synthesis strategies were applied to evaluate the chemical space around the essential pharmacophore groups R1 to R3 to obtain highly active and selective pyrrolidine derivatives as integrin α5β1 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.
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pyrrolidine derivativesSelective Integrin α5β1 AntagonistsStartingpeptidic ligandSAR datasynthesis strategiesvivo studiessulfonamide moietyR 3chemical spaceintegrin α5β1 antagonistspharmacophore groups R 1New Classintegrin α v β3animal modelsintegrin receptorsIntegrin selectivitymesitylene amide moietynonpeptidic ligandsmodulating selectivityR 3.