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.

Abstract

BACKGROUND AND PURPOSE:

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.

EXPERIMENTAL APPROACH:

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.

KEY RESULTS:

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.

CONCLUSIONS AND IMPLICATIONS:

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.

• Authors: M Ishimura, M Suda, K Morizumi, S Kataoka, T Maeda, S Kurokawa, Y Hiyama
• Journal: British journal of pharmacology (Br J Pharmacol) Vol. 153 Issue 4 Pg. 669-75 (Feb 2008) ISSN: 0007-1188 [Print] England
• PMID: 18037905 (Publication Type: Comparative Study, Journal Article)

Chemical References

• Acetates
• Anti-Asthmatic Agents
• Benzoates
• Benzoquinones
• Cyclopropanes
• Heptanoic Acids
• KP-496
• Leukotriene Antagonists
• Membrane Proteins
• Prostaglandin Antagonists
• Quinolines
• Receptors, Leukotriene
• Receptors, Thromboxane A2, Prostaglandin H2
• Sulfides
• Thiazoles
• seratrodast
• Leukotriene D4
• 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid
• Ovalbumin
• leukotriene D4 receptor
• montelukast

Topics

• 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid
• Acetates (pharmacology)
• Administration, Inhalation
• Administration, Oral
• Airway Obstruction (chemically induced, metabolism, physiopathology, prevention & control)
• Animals
• Anti-Asthmatic Agents (administration & dosage, metabolism, pharmacology)
• Benzoates (administration & dosage, metabolism, pharmacology)
• Benzoquinones (pharmacology)
• Bronchoconstriction (drug effects)
• Cyclopropanes
• Disease Models, Animal
• Dose-Response Relationship, Drug
• Drug Therapy, Combination
• Guinea Pigs
• Heptanoic Acids (pharmacology)
• Leukotriene Antagonists (administration & dosage, metabolism, pharmacology)
• Leukotriene D4
• Lung (drug effects, metabolism, physiopathology)
• Male
• Membrane Proteins (antagonists & inhibitors, metabolism)
• Ovalbumin
• Prostaglandin Antagonists (administration & dosage, metabolism, pharmacology)
• Quinolines (pharmacology)
• Receptors, Leukotriene (metabolism)
• Receptors, Thromboxane A2, Prostaglandin H2 (antagonists & inhibitors, metabolism)
• Respiratory Hypersensitivity (immunology, metabolism, physiopathology, prevention & control)
• Sulfides
• Thiazoles (administration & dosage, metabolism, pharmacology)
• Time Factors