A NOVEL SERIES OF L(2-PHENETHYL)AMINO]-2-OXOETHYL]BENZENE-CONTAINING LEUKOTRIENE B-4 ANTAGONISTS - INITIAL STRUCTURE-ACTIVITY-RELATIONSHIPS

This report describes the synthesis of a new class of LTB(4) receptor antagonists containing [2-[methyl(2-phenethyl)amino]-2-oxoethyl]benzen e as a key binding domain for interaction with high-affinity LTB(4) re ceptors. In addition to this binding domain, two other structural feat ures, an acid function and a lipophilic group, are also required by th ese compounds for high binding affinity, Our studies indicate that max imal binding affinity in this series is controlled by the spatial rela tionship of these groups relative to one another, The structure-activi ty relationships are discussed, The most potent compound in this chemi cal series, phenethyl)amino]-2-oxoethyl]-2-(benzyloxy)cinnamic acid (3 2), has an IC50 of 2 nM in a guinea pig spleen cell membrane assay, In the whale-cell human neutrophils binding assay, phenethyl)amino]-2-ox oethyl]-2-(benzyloxy)cinnamic acid (30) was the most potent compound w ith an IC50 of 50 nM.