Preface [Hot Topic: Perspective on VLA-4 Antagonists (Guest Editor: Jefferson W. Tilley)]

A number of studies appearing in the mid-1990s employing antibody reagents and gene ablation technologies offered promise for a role of VLA-4 in a number of inflammatory diseases including asthma, rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease, type I diabetes and atherosclosis. A brief summary and leading references are provided in reference [1]. These findings prompted a number of firms, among them Wyeth, Elan (then Athena Neurosciences), Merck, Biogen and Roche to initiate small molecule programs taking a number of different approaches that are detailed in this volume. Each of them has lead to the identification of important lead series providing either a clinical candidate or a clear path to one and highlights a number of issues, which have slowed progress in this area. All lead compounds incorporate carboxylic acids leading to generally poor oral absorption and particularly vexing has been the almost universally observed rapid hepatic clearance of unchanged drug via an acid transporter, limiting the duration of exposure. The animal disease model data reported herein suggest that there hurdles may be surmountable. Activated integrins are high molecular weight heterodimeric glycoproteins extending stalk-like from the cell surface. The ligand bindng domain is near the N-terminus some 100 Å from the cell membrane. Although it was widely known that affinity is subject to modulation through intracellular signaling (inside out) and ligand binding induces cytoskeletal responses (outside in signaling) the mechanism of these effects was unknown. The availability of the first x-ray structures of an integrin [2,3] combined with the creative work carried out in the Springer laboratories summarized in the Shimaoka and Springer paper provide important insights on these mechanisms and provide clues to further optimization of lead molecules. Finally, the recent reports in the New England Journal of Medicine on phase II clinical trials of the humanized anti-alpha4 integrin monoclonal antibody, natralizumab, in multiple sclerosis [4] and Crohn's disease [5] provide the first validation of the alpha4 integrins as relevant targets for human disease and increase our hopes that small molecule approaches such as those illustrated in this volume will lead to import new medicines in the coming years.