Discovery of novel p-arylthio cinnamides as antagonists of leukocyte function-associated antigen-1/intracellular adhesion molecule-1 interaction. 1. Identification of an additional binding pocket based on an anilino diaryl sulfide lead

The interaction between leukocyte function-associated antigen-1 (LFA-1), a member of the beta (2)-integrin family of adhesion molecules, and intracell ular adhesion molecule ICAM-1 (cd54) is thought to play a critical role in the inflammatory process. On the basis of an anilino diaryl sulfide screeni ng lead 1, in combination with pharmacophore analysis of other screening hi ts, we have identified an adjacent binding pocket. Subsequently, a p-etheny lcarbonyl linker was discovered to be optimal for accessing this binding si te. Solution-phase parallel synthesis enabled rapid optimization of the cin namides for this pocket. In conjunction with fine-tuning of the diaryl subs tituents, we discovered a novel series of potent, nonpeptide inhibitors of LFA-1/ICAM-1 interaction, exemplified by A-286982 (28h), which has IC50 val ues of 44 and 35 nM in an LFA-1/ICAM-1 binding assay and LFA-l-mediated cel lular adhesion assay, respectively.