title: (R)-2-[4-(quinolin-2-yl-methoxy)phenyl]-2-cyclopentyl] acetic acid (BAY x1005), a potent leukotriene synthesis inhibitor: effects on anti-IgE challenge in human airways.
abstract: Anti-IgE at a fixed dilution (1:1000) contracted human airways that had been pretreated with atropine (1 microM), indomethacin (3 microM) and chlorpheniramine (1 microM). This response was blocked by the potent leukotriene synthesis inhibitor BAY x 1005 ((R)-2-[4-(Quinolin-2-yl-methoxy)phenyl)-2-cyclopentyl acetic acid]. The leukotriene synthesis inhibitor MK-886 also blocked the contraction, but BAY x1005 was approximately 10-fold more potent than MK-886 (the IC50 values were 0.27 microM and 3.4 microM for BAY x1005 and MK-886, respectively). BAY x1005 (1 microM) did not alter LTD4 cumulative concentration-effect curves on human airways. Bronchial muscles derived from different levels of the respiratory tract released small quantities of LTE4 (proximal, 7.99 +/- 1.25 ng/g tissue wet wt.; distal, 13.12 +/- 4.46 ng/g tissue wet wt.). These basal levels were significantly increased when the preparations were challenged with a fixed dilution (1:1000) of anti-IgE (proximal, 21.84 +/- 5.33 ng/g tissue wet wt.; distal 72.13 +/- 30.70 ng/g tissue wet wt.). Indomethacin (3 microM) did not alter either the basal amounts or the levels of LTE4 measured during anti-IgE stimulation. However, BAY x1005 or MK-886 in the presence of indomethacin prevented the increase in LTE4 levels that were observed during anti-IgE challenge. In these protocols the IC50 values obtained were 0.18 microM and 1.42 microM for BAY x1005 and MK-886, respectively. These data demonstrate that BAY x1005 is a potent leukotriene synthesis inhibitor in human airways.
authors.affiliation: Centre Chirurgical Marie Lannelongue, Le Plessis-Robinson France.
authors.forename: I
authors.initials: I
authors.lastname: Gorenne
authors.forename: C
authors.initials: C
authors.lastname: Labat
authors.forename: J P
authors.initials: JP
authors.lastname: Gascard
authors.forename: X
authors.initials: X
authors.lastname: Norel
authors.forename: R
authors.initials: R
authors.lastname: Müller-Peddinghaus
authors.forename: K H
authors.initials: KH
authors.lastname: Mohrs
authors.forename: W A
authors.initials: WA
authors.lastname: Taylor
authors.forename: P J
authors.initials: PJ
authors.lastname: Gardiner
authors.forename: C
authors.initials: C
authors.lastname: Brink
mesh_terms: D001980:Bronchi / Q000187:drug effects*; D016084:Bronchoconstriction / Q000187:drug effects; D005260:Female; D006801:Humans; D007073:Immunoglobulin E / Q000276:immunology*; D066298:In Vitro Techniques; D007211:Indoles / Q000494:pharmacology; D007213:Indomethacin / Q000494:pharmacology; D007975:Leukotriene B4 / Q000037:antagonists & inhibitors*; D017999:Leukotriene E4 / Q000378:metabolism; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology*; D008297:Male; D011804:Quinolines / Q000494:pharmacology*; D002722:Chlorobenzenes
chemical_list: D007073:Immunoglobulin E; D007211:Indoles; D007213:Indomethacin; D007975:Leukotriene B4; D017999:Leukotriene E4; D016859:Lipoxygenase Inhibitors; D011804:Quinolines; C060893:MK-886; D002722:Chlorobenzenes; C079315:2-(4-(quinolin-2-yl-methoxy)phenyl)-2-cyclopentylacetic acid