Tyrosine modified analogues of the α4β7 integrin inhibitor biotin-R8ERY prepared via Click Chemistry: Synthesis and biological evaluation

Our continuing programme aiming at developing inhibitors of integrin α4β7, a key mediator of various inflammatory diseases, led us to synthesise a library of cell-permeable peptides based on the biotin-R8ERY∗ template, wherein the tyrosine residue has been modified by using the CuAAC reaction. The 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. Two of the synthesised peptidomimetics, analogues 11 and 14, are more active than our previously reported lead compound biotin-r9YDRREY at concentrations of 100 and 50 μM, with 14 exhibiting an IC50 of less than 10 μM.