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

Abstract

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) D₄ and thromboxane (TX) A₂ receptors were examined using the LTD₄- 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 LTD₄ 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 LTD₄ and TXA₂ receptors with pA₂ values of 8.64 and 8.23, respectively. The LTD₄ antagonistic activity of KP-496 was comparable to that of pranlukast and zafirlukast but was more potent than that of montelukast. The TXA₂ antagonistic activity of KP-496 was comparable to that of seratrodast. KP-496 and seratrodast also inhibited the prostaglandin (PG) D₂- and PGF_2α-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 LTD₄ and TXA₂ receptors. LTD₄ and TXA₂ 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.