Abstract
The discovery and SAR of a novel series of substituted 2,2-bisaryl-bicycloheptane inhibitors of 5-lipoxygenase activating protein (FLAP) are herein described. SAR studies have shown that 2,5-substitution on the exo-aryl group is optimal for potency. The most potent compounds in this series have an ortho-nitrogen aryl linked with a methyleneoxy as the 5-substituent and a polar group such as a urethane as the 2-substituent. One of the most potent compounds identified is the 5-benzothiazolymethoxy-2-pyridinylcarbamate derivative 2 (FLAP IC(50)=2.8 nM) which blocks 89% of ragweed induced urinary LTE(4) production in dogs (at an I.V. dose of 2.5 microg/kg/min). This compound inhibits calcium ionophore stimulated LTB(4) production in both human polymorphonuclear (PMN) leukocytes and human whole blood (IC(50)=2.0 and 33 nM, respectively).
MeSH terms
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5-Lipoxygenase-Activating Proteins
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Ambrosia / chemistry
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Animals
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Bridged Bicyclo Compounds / chemical synthesis
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Bridged Bicyclo Compounds / pharmacology*
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Carrier Proteins / antagonists & inhibitors*
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Carrier Proteins / metabolism
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Dogs
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Heptanes / chemical synthesis
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Heptanes / pharmacology*
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Humans
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Indoles / metabolism
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Indoles / pharmacology
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Iodine Radioisotopes / metabolism
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Leukotriene D4 / urine
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Lipoxygenase Inhibitors / pharmacology*
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Membrane Proteins / antagonists & inhibitors*
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Membrane Proteins / metabolism
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Molecular Structure
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Neutrophils / drug effects
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Quinolines / metabolism
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Quinolines / pharmacology
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Stereoisomerism
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Structure-Activity Relationship
Substances
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5-Lipoxygenase-Activating Proteins
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ALOX5AP protein, human
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Bridged Bicyclo Compounds
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Carrier Proteins
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Heptanes
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Indoles
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Iodine Radioisotopes
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Lipoxygenase Inhibitors
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Membrane Proteins
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Quinolines
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MK 0591
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L 691831
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Leukotriene D4