[摘要]：The development of antagonists to the alpha 4 integrin family of cell adhesion molecules has been an active area of pharmaceutical research to treat inflammatory and autoimmune diseases. Presently being tested in human clinical trials are compounds selective for alpha 4 beta 1 (VLA-4) as well as several dual antagonists that inhibit both alpha 4 beta 1 and alpha 4 beta 7. The value of a dual versus a selective small molecule antagonist as well as the consequences of inhibiting different affinity states of the alpha 4 integrins have been debated in the literature. Here, we characterize TBC3486, a N,N-disubstituted amide, which represents a unique structural class of non-peptidic, small molecule VLA-4 antagonists. Using a variety of adhesion assay formats as well as flow cytometry experiments using mAbs specific for certain activation-dependent integrin epitopes we demonstrate that TBC3486 preferentially targets the high affinity conformation of alpha 4 beta 1 and behaves as a ligand mimetic. The antagonist is capable of blocking integrin-dependent T-cell co-activation in vitro as well as proves to be efficacious in vivo at low doses in two animal models of allergic inflammation. These data suggest that a small molecule alpha 4 integrin antagonist selective for alpha 4 beta 1 over alpha 4 beta 7 and, specifically, selective for the high affinity conformation of alpha 4 beta 1 may prove to be an effective therapy for multiple inflammatory diseases in humans. (c) 2010 Elsevier Inc. All rights reserved.
