Novel p-arylthio cinnamides as antagonists of leukocyte function-associated antigen-1/intracellular adhesion molecule-1 interaction. 2. Mechanism of inhibition and structure-based improvement of pharmaceutical properties

The interaction between leukocyte function-associated antigen-1 (LFA-1) and intracellular adhesion molecule-1 (ICAM-1) has been implicated in inflamma tory and immune diseases. Recently, a novel. series of p-arylthio cinnamide s has been described as potent antagonists of the LFA-1/ICAM-1 interaction. These compounds were found to bind to the I domain of LFA-1 using two-dime nsional NMR spectroscopy of N-15-labeled LFA-I I domain. On the basis of NO E studies between compound I and the I domain of LFA-1, a model of the comp lex was constructed. This model revealed that compound I does not directly inhibit ICAM-1 binding by interacting with the metal ion dependent adhesion site (MIDAS). Instead, it binds to the previously proposed I domain allost eric site (IDAS) of LFA-1 and likely modulates the activation of LFA-1 thro ugh its interaction with this regulatory site. A fragment-based NMR screeni ng strategy was applied to identify small, more water-soluble ligands that bind to a specific region of the IDAS. When incorporated into the parent ci nnamide template, the resulting analogues exhibited increased aqueous solub ility and improved pharmacokinetic profiles in rats, demonstrating the powe r of this NMR-based screening approach for rapidly modifying high-affinity ligands.