Discovery of novel p-arylthio cinnamides as antagonists of leukocyte function-associated antigen-1/intercellular adhesion molecule-1 interaction. 4. Structure-activity relationship of substituents on the benzene ring of the cinnamide

We have shown that p-arylthio cinnamides can inhibit the interaction of LFA -1 and ICAM-1, which is involved in cell adhesion and the inflammatory proc ess. We now show that 2,3-disubstitution on the aryl portion of the cinnami de results in enhanced activity over mono substitution on the ring. The bes t 2,3-substituents were chlorine and trifluoromethyl groups. Compounds 39 a nd 40 which contain two CF3 groups have IC50 values of 0.5 and 0.1 nM, resp ectively, in inhibiting JY8 cells expressing LFA-1 on their surface, from a dhering to ICAM-1. The structure-activity relationship (SAR) was examined u sing an NMR based model of the LFA-1 I domain/compound 31 complex. One of o ur compounds (38) was able to reduce cell migration in two different in viv o experiments.