DESIGN, SYNTHESIS, AND PHARMACOLOGICAL EVALUATION OF POTENT XANTHONE DICARBOXYLIC-ACID LEUKOTRIENE-B4 RECEPTOR ANTAGONISTS

In an effort to develop increasingly potent and specific leukotriene B 4(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 maj or conformationally-restricted analogues of benzophenone dicarboxylic acids previously shown to antagonize the activation of human neutrophi ls 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 chemiluminesce nce (IC50, 55 +/- 11 nM), aggregation (IC50, 133 +/- 42 nM), and chemo taxis (IC50, 899 +/- 176 nM). The compound was a poor antagonist of or myl-L-methionyl-L-leucyl-L-phenylalanine-induced chemiluminescence (IC 50, 1599 +/- 317 nM) and aggregation (IC50, 2166 +/- 432 nM), indicati ng specificity in the inhibition of LTB4-stimulated events. Compound 3 2 (LY210073), which was completely devoid of agonist activity, appears to be one of the strongest inhibitors of LTB4 receptor binding report ed so far.