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Abstract
The α4 integrins, α4β1 (VLA-4) and α4β7, are heterodimeric cell-surface proteins expressed on leukocytes involved in both cell-cell and cell-matrix interactions. These two integrins are key regulators of physiologic and pathologic responses in inflammation and autoimmune disease. In particular, their central role in animal models of allergic lung disease has been well documented, and suggests a key role in human asthma. In addition, integrins are proven valid targets for small molecule drugs, following the development of both parenteral and orally active antagonists of platelet integrin αIIbβ3, and more recently, integrin β3. Therefore, there is a significant drive to develop small molecule inhibitors of α4 integrins for autoimmune diseases in general, and asthma in particular. The biology of α4 integrins in asthma has been recently reviewed, as has early work on the chemistry of α4 integrin antagonists. Here we summarise the recent rapid advances in this arena, particularly in the chemistry of α4 integrin small molecule antagonists, with emphasis on asthma as a clinical target.