Effects of KP-496, a novel dual antagonist for leukotriene D4 and thromboxane A2 receptors, on contractions induced by various agonists in the guinea pig trachea.
BACKGROUND
A dry powder inhaler of KP-496 is currently in clinical development in Japan as an anti-asthmatic agent. The aim of this study was to evaluate the in vitro pharmacological profile of KP-496.


METHODS
The antagonistic activities of KP-496 for leukotriene (LT) D(4) and thromboxane (TX) A(2) receptors were examined using the LTD(4)- and U46619-induced contractions of the isolated guinea pig trachea. The selectivity of KP-496 was examined using various agonist-induced contractions in the isolated guinea pig trachea.


RESULTS
KP-496 produced parallel rightward shifts of the LTD(4) and U46619 concentration-response curves in a concentration-dependent manner. Schild plot analyses of the antagonistic activities of KP-496 demonstrated that it is a competitive antagonist for LTD(4) and TXA(2) receptors with pA(2) values of 8.64 and 8.23, respectively. The LTD(4) antagonistic activity of KP-496 was comparable to that of pranlukast and zafirlukast but was more potent than that of montelukast. The TXA(2) antagonistic activity of KP-496 was comparable to that of seratrodast. KP-496 and seratrodast also inhibited the prostaglandin (PG) D(2)- and PGF(2alpha)-induced contractions of the isolated guinea pig trachea. KP-496 had no effect on the histamine-, acetylcholine-, serotonin- and substance P-induced contractions of the isolated guinea pig trachea.


CONCLUSIONS
These results indicate that KP-496 is a selective dual antagonist for LTD(4) and TXA(2) receptors. LTD(4) and TXA(2) play important roles in asthma, and antagonists for these mediators are being used for the treatment of asthma. Thus, KP-496 is expected to become a novel potent therapeutic agent for asthma.
Ishimura
Masakazu
M
Pharmacology Department, Central Research Laboratories, Kaken Pharmaceutical Co., Ltd., Kyoto, Japan. ishimura_masakazu@kaken.co.jp
Kataoka
Sayuri
S
Suda
Masahiro
M
Maeda
Takashi
T
Hiyama
Yoshiyuki
Y
D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid / Q000037:antagonists & inhibitors / Q000494:pharmacology; D000085:Acetates / Q000494:pharmacology; D000109:Acetylcholine / Q000494:pharmacology; D000420:Albuterol / Q000494:pharmacology; D000818:Animals; D001285:Atropine / Q000494:pharmacology; D016227:Benzoquinones / Q000494:pharmacology; D002217:Carbachol / Q000494:pharmacology; D002867:Chromones / Q000494:pharmacology; D003521:Cyclopropanes; D015237:Dinoprost / Q000037:antagonists & inhibitors / Q000494:pharmacology; D004353:Drug Evaluation, Preclinical; D006168:Guinea Pigs; D006538:Heptanoic Acids / Q000494:pharmacology; D006632:Histamine / Q000494:pharmacology; D066298:In Vitro Techniques; D007211:Indoles; D007213:Indomethacin / Q000494:pharmacology; D007650:Ketanserin / Q000494:pharmacology; D007665:Ketotifen / Q000494:pharmacology; D020024:Leukotriene Antagonists / Q000494:pharmacology*; D017998:Leukotriene D4 / Q000819:agonists / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects*; D009130:Muscle, Smooth / Q000187:drug effects*; D048448:Phenylcarbamates; D011208:Powders; D017265:Procaterol / Q000494:pharmacology; D011448:Prostaglandin Antagonists / Q000494:pharmacology*; D015230:Prostaglandin D2 / Q000037:antagonists & inhibitors / Q000494:pharmacology; D011804:Quinolines / Q000494:pharmacology; D044244:Receptors, Thromboxane A2, Prostaglandin H2 / Q000819:agonists / Q000037:antagonists & inhibitors*; D012701:Serotonin / Q000494:pharmacology; D013373:Substance P / Q000494:pharmacology; D013440:Sulfides; D013449:Sulfonamides; D014105:Tosyl Compounds / Q000494:pharmacology; D014132:Trachea / Q000187:drug effects*; D014364:Tryptophan / Q000031:analogs & derivatives / Q000494:pharmacology
D000085:Acetates; D016227:Benzoquinones; D002867:Chromones; D003521:Cyclopropanes; D006538:Heptanoic Acids; D007211:Indoles; D020024:Leukotriene Antagonists; D048448:Phenylcarbamates; D011208:Powders; D011448:Prostaglandin Antagonists; D011804:Quinolines; D044244:Receptors, Thromboxane A2, Prostaglandin H2; D013440:Sulfides; D013449:Sulfonamides; D014105:Tosyl Compounds; C086089:3,5-bis(trifluoromethyl)benzyl N-acetyltryptophan; D012701:Serotonin; D013373:Substance P; C060230:seratrodast; D017998:Leukotriene D4; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D001285:Atropine; D006632:Histamine; D014364:Tryptophan; D002217:Carbachol; D007650:Ketanserin; D015237:Dinoprost; C093875:montelukast; D000109:Acetylcholine; D000420:Albuterol; D015230:Prostaglandin D2; C047681:pranlukast; D007665:Ketotifen; D017265:Procaterol; D007213:Indomethacin; C062735:zafirlukast