BENZOPHENONE DICARBOXYLIC-ACID ANTAGONISTS OF LEUKOTRIENE-B4 .2. STRUCTURE-ACTIVITY-RELATIONSHIPS OF THE LIPOPHILIC SIDE-CHAIN

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 LTB4receptor 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]LTB4binding 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 LTB to its receptor on intact human neutrophils. The most active compound from this series, 84 (LY223982), bound to the LTB4receptor with an affinity approaching that of the agonist. © 1990, American Chemical Society. All rights reserved.