LY-213024

A series of lipophilic benzophenone dicarboxylic acid derivatives were found to inhibit the binding of the potent chemotaxin leukotriene B4 (LTB4) to its receptor on intact human neutrophils. Activity at the LTB4 receptor was determined by using a [3H]LTB4-binding assay. The structure-activity relationship for the lipophilic side chain was systematically investigated. Compounds with n-alkyl side chains of varying lengths were prepared and tested. Best inhibition of [3H]LTB4 binding was observed with the n-decyl derivative. Analogues with alkyl chains terminated with an aromatic ring showed improved activity. The 6-phenylhexyl side chain was optimal. Substitution on the terminal aromatic ring was also evaluated. Methoxyl, methylsulfinyl, and methyl substituents greatly enhanced the activity of the compound. For a given substituent, the para isomer had the best activity. Thus the nature of the lipophilic side chain can greatly influence the ability of the compounds to inhibit the binding of LTB4 to its receptor on intact human neutrophils. The most active compound from this series, 84 (LY223982), bound to the LTB4 receptor with an affinity approaching that of the agonist.

Lipophilic benzophenone dicarboxylic acids have been shown to be inhibitors of the binding of LTB₄ to its receptors on intact human neutrophils (Gapinski et al., 1990).Structure-activity relations indicated that maximum activity was achieved when an acid group was attached at the meta position of each ring.In this report, the conformation of these inhibitors that binds best to the LTB₄ receptor was determinedInhibition concentration profiles of 4 rigid xanthone isomers that mimicked the 4 major conformational states of this type of benzophenone dicarboxylic acid were compared.LY264086, 3-[4-[7-carboxy-3-[decyloxy]-9-oxo-9H-xanthene]]propanoic acid, was the most potent inhibitor.The distance between the 2 carboxyl groups in this isomer was 9.8 Å, implying that the 2 acid binding sites on the receptor are separated by similar dimensions.Mol. modeling studies with low energy conformers of the xanthone isomers and LTB₄ suggested a configuration of the agonist when it is bound to the receptor, but did not exclude all other possibilities.These experiments further support the existence of 2 acid-binding sites on the human neutrophil LTB₄ receptor.