Very late antigen-4 integrin antagonists

Background: Together with 2 integrins and selectins, alpha 4 integrins mediate lymphocyte arrest, extravasation and migration to sites of inflammation. They have been validated as therapeutic targets for inflammatory diseases and, in addition to the marketed anti-alpha 4 antibody natalizumab, numerous small-molecule antagonists have been discovered as candidate drugs. Objective: The present review summarizes work establishing natalizumab as an agent for the treatment of multiple sclerosis and Crohn's disease as well as the safety concerns caused by the development of progressive multifocal leukoencephalopathy in three patients during natalizumab trials. Early development of small-molecule alpha 4 integrin antagonists was limited by their characteristic poor pharmacokinetic properties, but the new generations of compounds discussed in this manuscript have successfully addressed this issue and several are currently in clinical trial for multiple sclerosis. Methods: A Scifinder search of the Chemistry Abstracts database from 2003 to 2008 was augmented by a search of the Investigational Drugs Database (IDDB). Results: Although safety concerns and pharmacokinetic issues have caused many companies to discontinue with this area of research, a number of companies continue to pursue this target. Structures and selected data, where available, for compounds reported since the beginning of 2003 are highlighted in this review.