Structure-activity relationship studies of a series of peptidomimetic ligands for α₄β₁ integrin on Jurkat T-leukemia cells

α₄β₁ integrin is a therapeutic target for inflammation, autoimmune diseases, and lymphoid cancers. A series of peptidomimetic ligands based on the Nle-D-I motif have been synthesized and their binding affinities (IC₅₀) to activated α ₄β₁ integrin on Jurkat T-leukemia cells have been determined using a cell adhesion assay. One of the 51 ligands, 18, has been determined to have an IC₅₀ of 0.6 nM and has a more than twofold increase of binding affinity than the initial lead compound 1. Extensive SAR studies provide important information for further ligand optimization, which has served as a foundation for studies that ultimately led to identification of a potent ligand with an IC₅₀ of 2 pM.