Synthesis and biological evaluation of tyrosine modified analogues of the α4β7 integrin inhibitor biotin-R8ERY

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 synthesis of a small library of cell-permeable β7 integrin inhibitors based on the peptide biotin-R8ERY is reported, in which the tyrosine residue has been modified by using the Suzuki-Miyaura cross-coupling reaction. 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. All of the synthesised peptidomimetics are more active than our previously reported lead compound biotin-R8ERY with two of the analogues, 6 and 7, exhibiting IC50 values of <15 μM.

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