A novel series of [2-[methyl(2-phenethyl)amino]-2-oxoethyl]benzene-containing leukotriene B4 antagonists : Initial structure-activity relationships

This report describes the synthesis of a new class of LTB4 receptor antagonists containing [2-[methyl(2-phenethyl)amino]-2-oxoethyl]benzene as a key binding domain for interaction with high-affinity LTB4 receptors. In addition to this binding domain, two other structural features, an acid function and a lipophilic group, are also required by these compounds for high binding affinity. Our studies indicate that maximal binding affinity in this series is controlled by the spatial relationship of these groups relative to one another. The structure−activity relationships are discussed. The most potent compound in this chemical series, (E)-5-[2-[methyl(2-phenethyl)amino]-2-oxoethyl]-2-(benzyloxy)cinnamic acid (32), has an IC50 of 2 nM in a guinea pig spleen cell membrane assay. In the whole-cell human neutrophils binding assay, (Z)-5-[2-[methyl(2-phenethyl)amino]-2-oxoethyl]-2-(benzyloxy)cinnamic acid (30) was the most potent compound with an IC50 of 50 nM.