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  • Title: Design, synthesis, and pharmacological evaluation of potent xanthone dicarboxylic acid leukotriene B4 receptor antagonists.
    Author: Jackson WT, Boyd RJ, Froelich LL, Gapinski DM, Mallett BE, Sawyer JS.
    Journal: J Med Chem; 1993 Jun 11; 36(12):1726-34. PubMed ID: 8389876.
    Abstract:
    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.
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