Design, Synthesis, and Pharmacological Evaluation of Potent Xanthone Dicarboxylic Acid Leukotriene B4 Receptor Antagonists

Article abstract of DOI:10.1021/jm00064a006

In an effort to develop increasingly potent and specific leukotriene B4(LTB4) receptor antagonists, several xanthone dicarboxylic acids were synthesized and evaluated.Two separate synthetic routes were used to construct a xanthone nucleus containing a regiospecific orientation of each carboxylic acid pharmacophore.These compounds represent the major conformationally-restricted analogues of benzophenone dicarboxylic acids previously shown to antagonize the activation of human neutrophils by LTB4.The most potent agent was compound 32, which inhibited the specific binding of <3H>LTB4 to receptors on intact human neutrophils (IC50, 6.2 +/- 0.1 nM), LTB4-induced luminol-dependent chemiluminescence (IC50, 55 +/- 11 nM), aggregation (IC50, 133 +/- 42 nM), and chemotaxis (IC50, 899 +/- 176 nM).The compound was a poor antagonist of N-formyl-L-methionyl-L-leucyl-L-phenylalanine-induced chemiluminescence (IC50, 1599 +/- 317 nM) and aggregation (IC50, 2166 +/- 432 nM), indicating specificity in the inhibition of LTB4-stimulated events.Compound 32(LY210073), which was completely devoid of agonist activity, appears to be one of the strongest inhibitors of LTB4 receptor binding reported so far.