Benzophenone Dicarboxylic Acid Antagonists of Leukotriene B4. 2. Structure-Activity Relationships of the Lipophilic Side Chain

Article abstract of DOI:10.1021/jm00172a020

A series of lipophilic benzophenone dicarboxylic acid derivatives were found to inhibit the binding of the potent chemotoxin 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 the affinity approaching that of the agonist.