Discovery of potent antagonists of leukocyte function-associated antigen-1/intercellular adhesion molecule-1 interaction. 3. Amide (C-ring) structure-activity relationship and improvement of overall properties of arylthio cinnamides

The interaction of LFA-1 and ICAM-1 plays an important role in the cell adh esion process. On the basis of previously reported SAR and structural infor mation on the binding of our p-arylthiocinnamide series to LFA-1, we have i dentified the cyclic amide (C-ring) as a site for modification. Improvement in potency and, more importantly, in the physical properties and pharmacok inetic profiles of the leading compounds resulted from this modification. O ne of the best compounds (11f) is also shown to reduce myocardial infarct s ize in rat.