STRUCTURE-ACTIVITY-RELATIONSHIPS STUDY OF 2 SERIES OF LEUKOTRIENE B-4ANTAGONISTS - NOVEL INDOLYL AND NAPHTHYL COMPOUNDS SUBSTITUTED WITH A2-[METHYL(2-PHENETHYL)AMINO]-2-OXOETHYL SIDE-CHAIN

N-Methyl-N-phenethylphenylacetamide has been reported to be a key bind ing domain to LTB(4) receptors, Here we describe the synthesis and str ucture-activity relationship (SAR) studies of two new series of LTB(4) receptor antagonists in which the phenyl ring of this receptor bindin g domain is replaced with indole and naphthalene, respectively. Result s of these studies indicate that, in addition to the 2-[methyl(2-phene thyl)amino]-2-oxoethyl moiety, the presence of an acid group and a lip ophilic side chain, as well as the spatial relationship of these three functions, is crucial for high binding affinity with LTB(4) receptors . Our SAR studies also reveal that an arenecarboxylic acid, or an enoi c acid in which the carboxyl group is conjugated with the central ring , is the preferred polar group, The lipophilic side chain of the napht hyl series was found to tolerate minor variations, ranging from a phen ylmethoxy group to phenyl and alkyloxy groups. The most active compoun ds are hyl-3-[1-[2-[methyl(2-phenethyl)amino]-2-oxothyl]- 5-(phenylmet hoxy)indol-3-yl]propenoic acid (4g) of the indolyl series and 4-[2-[me thyl(2- phenethyl)amino]-2-oxoethyl]-8-(phenylmethoxy)-2- naphthalenec arboxylic acid (2a) or the naphthyl series, with. IC50 of 8 and 4.7 nM respectively, in the receptor binding assay using intact human neutro phils.