Design and synthesis of potent and selective alpha(4)beta(7) integrin antagonists

Interactions of the integrins alpha (4)beta (7) with its cognate ligand muc osal addressin cell adhesion molecule-1 (MAdCAM-1) play a crucial role in t he development of mucosa-associated lymphoid organs, in the generation of m ucosal immune responses, and in diverse pathological processes such as chro nic inflammatory bowel disease and type I diabetes. Using a previously deve loped spatial screening technique we describe the development of potent and selective alpha (4)beta (7) integrin antagonists based on the domain 1 Leu -Asp-Thr (LDT) sequence of MAdCAM-1 that is essential for alpha (4)beta (7) integrin binding. A library of homodetic cyclic penta- and hexapeptides wa s synthesized presenting the pharmacophoric LDT-sequence in different confo rmations. The cyclic hexapeptide P10 cyclo(Leu-Asp-Thr-Ala-D-Pro-Ala) inhib its alpha (4)beta (7) integrin mediated cell adhesion to MAdCAM-1 effective ly. Further optimization of the lead structure P10 resulted in cyclic hexap eptides with enhanced activity. The compounds P25 cyclo(Leu-Asp-Thr-Ala-D-P ro-Phe), P28 cyclo(Leu-Asp-Thr-Asp-D-Pro-Phe), P29 cyclo(Leu-Asp-Thr-Asp-D- Pro-His), and P30 cyclo(Leu-Asp-Thr-Asp-D-Pro-Tyr) strongly inhibited alpha (4)beta (7) integrin mediated cell adhesion to MAdCAM-1, but they did not affect binding of the closely related alpha (4)beta (1) integrin to VCAM-1.