(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

I Gorenne, C Labat, JP Gascard, X Norel, R Muller-Peddinghaus, KH Mohrs, WA Taylor, PJ Gardiner and C Brink

Centre Chirurgical Marie Lannelongue, Le Plessis-Robinson France.

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.

Volume 268, Issue 2, pp. 868-872, 02/01/1994
Copyright © 1994 by American Society for Pharmacology and Experimental Therapeutics

This article has been cited by other articles:

				R. Malaviya, C.-L. Chen, C. Navara, R. Malaviya, X.-P. Liu, M. Keenan, B. Waurzyniak, and F. M. Uckun Treatment of Allergic Asthma by Targeting Janus Kinase 3-Dependent Leukotriene Synthesis in Mast Cells with 4-(3',5'-Dibromo-4'-hydroxyphenyl)amino-6,7-dimethoxyquinazoline (WHI-P97) J. Pharmacol. Exp. Ther., December 1, 2000; 295(3): 912 - 926. [Abstract] [Full Text]

				J H Calvet, J-P Gascard, S Delamanche, and C Brink Airway epithelial damage and release of inflammatory mediators in human lung parenchyma after sulfur mustard exposure Human and Experimental Toxicology, February 1, 1999; 18(2): 77 - 81. [Abstract] [PDF]

				I. Gorenne, C. Labat, J.-P. Gascard, X. Norel, N. Nashashibi, and C. Brink Leukotriene D4 Contractions in Human Airways are Blocked by SK&F 96365, an Inhibitor of Receptor-Mediated Calcium Entry J. Pharmacol. Exp. Ther., February 1, 1998; 284(2): 549 - 552. [Abstract] [Full Text]