Design, synthesis, and pharmacological evaluation of potent xanthone dicarboxylic acid leukotriene B4 receptor antagonists.
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.
Jackson
W T
WT
Lilly Research Laboratories, Eli Lilly & Co., Indianapolis, Indiana 46285.
Boyd
R J
RJ
Froelich
L L
LL
Gapinski
D M
DM
Mallett
B E
BE
Sawyer
J S
JS
D001577:Benzophenones / Q000494:pharmacology; D003998:Dicarboxylic Acids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D015195:Drug Design; D006801:Humans; D007975:Leukotriene B4 / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000494:pharmacology; D008163:Luminescent Measurements; D008165:Luminol / Q000494:pharmacology; D015394:Molecular Structure; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000494:pharmacology; D009504:Neutrophils / Q000378:metabolism; D011971:Receptors, Immunologic / Q000037:antagonists & inhibitors* / Q000378:metabolism; D018102:Receptors, Leukotriene B4; D014966:Xanthenes / Q000138:chemical synthesis* / Q000737:chemistry* / Q000494:pharmacology; D044004:Xanthones
D001577:Benzophenones; D003998:Dicarboxylic Acids; D011971:Receptors, Immunologic; D018102:Receptors, Leukotriene B4; D014966:Xanthenes; D044004:Xanthones; C065916:LY 223982; C081670:LY 210073; D007975:Leukotriene B4; D009240:N-Formylmethionine Leucyl-Phenylalanine; D008165:Luminol; C009689:xanthone