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.
OBJECTIVE
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.


METHODS
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.


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
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.
Pharmacology Department, Central Research Laboratories, Kaken Pharmaceutical Co. Ltd, Kyoto, Japan. ishimura_masakazu@kaken.co.jp
M
M
Ishimura
M
M
Suda
K
K
Morizumi
S
S
Kataoka
T
T
Maeda
S
S
Kurokawa
Y
Y
Hiyama
D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D000085:Acetates / Q000494:pharmacology; D000280:Administration, Inhalation; D000284:Administration, Oral; D000402:Airway Obstruction / Q000139:chemically induced / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*; D000818:Animals; D018927:Anti-Asthmatic Agents / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology*; D001565:Benzoates / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology*; D016227:Benzoquinones / Q000494:pharmacology; D016084:Bronchoconstriction / Q000187:drug effects*; D003521:Cyclopropanes; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D006168:Guinea Pigs; D006538:Heptanoic Acids / Q000494:pharmacology; D020024:Leukotriene Antagonists / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology*; D017998:Leukotriene D4; D008168:Lung / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D008565:Membrane Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010047:Ovalbumin; D011448:Prostaglandin Antagonists / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology*; D011804:Quinolines / Q000494:pharmacology; D018077:Receptors, Leukotriene / Q000378:metabolism; D044244:Receptors, Thromboxane A2, Prostaglandin H2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012130:Respiratory Hypersensitivity / Q000276:immunology / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*; D013440:Sulfides; D013844:Thiazoles / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology*; D013997:Time Factors
D000085:Acetates; D018927:Anti-Asthmatic Agents; D001565:Benzoates; D016227:Benzoquinones; D003521:Cyclopropanes; D006538:Heptanoic Acids; C528276:KP-496; D020024:Leukotriene Antagonists; D008565:Membrane Proteins; D011448:Prostaglandin Antagonists; D011804:Quinolines; D018077:Receptors, Leukotriene; D044244:Receptors, Thromboxane A2, Prostaglandin H2; D013440:Sulfides; D013844:Thiazoles; C060230:seratrodast; D017998:Leukotriene D4; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D010047:Ovalbumin; C083169:leukotriene D4 receptor; C093875:montelukast