Synthesis and SAR of a Library of Cell-Permeable Biotin-R8ERY* Peptidomimetics Inhibiting α4β7 Integrin Mediated Adhesion of TK-1 Cells to MAdCAM-1-Fc

Abstract

The α4β7 integrin is a well‐known target for the development of drugs against various inflammatory disease states including inflammatory bowel disease, type 1 diabetes, and multiple sclerosis. The β7 subunit contains the cell adhesion regulatory domain (CARD) motif YDRREY within its cytoplasmic domain, which is an effective peptide agent for inhibiting T-cell adhesion. The synthesis of a library of cell-permeable β7 integrin inhibitors based on the shortened biotin-R8ERY (R8 = (l-arginine)8) motif is reported, wherein the tyrosine residue has been modified. The synthesised peptidomimetics were evaluated in a cell adhesion assay and shown to inhibit Mn2+-activated adhesion of mouse TK-1 T-cells to mouse MAdCAM-1. Several analogues exhibited improved activity to that of the tyrosine-containing lead compound 1 (biotin-R8ERY). Specifically, analogues 4, 10, and 22 bearing a 4-chloro, a 4-nitro, and a 3,3-diphenyl substituent showed an increase in activity of approximately two-fold compared with that of the initial lead compound. The six most active compounds of the tested series had IC50’s between 25 and 50 μM.