Effects of KP-496, a novel dual antagonist at the cysteinyl leukotriene receptor 1 and the thromboxane A(2) receptor, on airway obstruction in guinea pigs

• Published in: British journal of pharmacology Vol. 153; no. 4; p. 669
• Main Authors: Ishimura, M, Suda, M, Morizumi, K, Kataoka, S, Maeda, T, Kurokawa, S, Hiyama, Y
• Format: Journal Article
• Language: English
• Published: England 01.02.2008
• Subjects: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Acetates - pharmacology; Administration, Inhalation; Administration, Oral; Airway Obstruction - chemically induced; Airway Obstruction - metabolism; Airway Obstruction - physiopathology; Airway Obstruction - prevention & control; Animals; Anti-Asthmatic Agents - administration & dosage; Anti-Asthmatic Agents - metabolism; Anti-Asthmatic Agents - pharmacology; Benzoates - administration & dosage; Benzoates - metabolism; Benzoates - pharmacology; Benzoquinones - pharmacology; Bronchoconstriction - drug effects; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Therapy, Combination; Guinea Pigs; Heptanoic Acids - pharmacology; Leukotriene Antagonists - administration & dosage; Leukotriene Antagonists - metabolism; Leukotriene Antagonists - pharmacology; Leukotriene D4; Lung - drug effects; Lung - metabolism; Lung - physiopathology; Male; Membrane Proteins - antagonists & inhibitors; Membrane Proteins - metabolism; Ovalbumin; Prostaglandin Antagonists - administration & dosage; Prostaglandin Antagonists - metabolism; Prostaglandin Antagonists - pharmacology; Quinolines - pharmacology; Receptors, Leukotriene - metabolism; Receptors, Thromboxane A2, Prostaglandin H2 - antagonists & inhibitors; Receptors, Thromboxane A2, Prostaglandin H2 - metabolism; Respiratory Hypersensitivity - immunology; Respiratory Hypersensitivity - metabolism; Respiratory Hypersensitivity - physiopathology; Respiratory Hypersensitivity - prevention & control; Thiazoles - administration & dosage; Thiazoles - metabolism; Thiazoles - pharmacology; Time Factors
• ISSN: 0007-1188; 1476-5381
• DOI: 10.1038/sj.bjp.0707602

KP-496 is a novel dual antagonist for cysteinyl leukotriene receptor 1 (CysLT(1)) and thromboxane A(2) (TXA(2)) receptor (TP). The aim of this study was to evaluate the pharmacological profile of inhaled KP-496 and its effects on airway obstruction. Antagonist activities of inhaled KP-496 were investigated using bronchoconstriction induced in guinea pigs by LTD(4) or U46619, a stable TXA(2) mimetic. Guinea pigs sensitized with injections of ovalbumin were used to assess the effects of inhaled KP-496 on bronchoconstriction induced by antigen (i.v.). Another set of guinea pigs were sensitized and challenged with ovalbumin by inhalation and the effects of inhaled KP-496 on immediate and late airway responses and airway hyperresponsiveness were investigated. KP-496 significantly inhibited LTD(4)- and U46619-induced bronchoconstriction in a dose-dependent manner. The inhibitory effects of KP-496 (1%) were comparable to those of montelukast (a CysLT(1) antagonist, p.o., 0.3 mg kg(-1)) or seratrodast (a TP antagonist, p.o., 3 mg kg(-1)). KP-496 (1%) and oral co-administration of montelukast (10 mg kg(-1)) and seratrodast (20 mg kg(-1)) significantly inhibited antigen-induced bronchoconstriction, whereas administration of montelukast or seratrodast separately did not inhibit antigen-induced bronchoconstriction. KP-496 exhibited dose-dependent and significant inhibitory effects on the immediate and late airway responses and airway hyperresponsiveness following antigen challenge. KP-496 exerts effects in guinea pigs which could be beneficial in asthma. These effects of KP-496 were greater than those of a CysLT(1) antagonist or a TP antagonist, in preventing antigen-induced airway obstruction.