Structure–activity relationship of ortho- and meta-phenol based LFA-1 ICAM inhibitors

LFA-1 ICAM inhibitors based on ortho- and meta-phenol templates were designed and synthesized by Mitsunobu chemistry. The selection of targets was guided by X-ray co-crystal data, and led to compounds which showed an up to 30-fold increase in potency over reference compound 1 in the LFA-1/ICAM1-Ig assay. The most active compound exploited a new hydrogen bond to the I-domain and exhibited subnanomolar potency.

Graphical abstractX-ray co-crystal data assisted the design of LFA-1 ICAM inhibitors based on ortho- and meta-phenol templates, leading to a compound which exploited a new hydrogen bond to the I-domain and which exhibited subnanomolar potency in the LFA-1/ICAM1-Ig assay.Figure optionsDownload full-size imageDownload as PowerPoint slide