Effects of KP‐496, a novel dual antagonist at the cysteinyl leukotriene receptor 1 and the thromboxane A₂ 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 À1 ) or seratrodast (a TP antagonist, p.o., 3 mg kg À1 ). KP-496 (1%) and oral co-administration of montelukast (10 mg kg À1 ) and seratrodast (20 mg kg À1 ) 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.

The Effects of Inhaled KP-496, a Novel Dual Antagonist for Cysteinyl Leukotriene Receptor and Thromboxane A₂ Receptor, on Allergic Asthmatic Responses in Guinea Pigs

“…Except for IAR, these results are consistent with our previous report [24] . Since IAR has been considered a form of bronchoconstriction caused by histamine and lipid mediators such as cysLTs and TXA 2 , the discrepancy in findings between this and our previous report [24] about IAR might have mainly resulted from the fact that the animals were treated with or without H 1 antagonist before OA provocation. This finding is consistent with the results observed for RS-601 [22] .…”

“…The antagonistic activities of KP-496 for both LTD 4 and TXA 2 are comparable to the cysLT receptor antagonists and TP antagonist already launched [23] . Furthermore, our previous study [24] demonstrated that inhaled KP-496 significantly inhibited antigen-induced bronchoconstriction, while sufficient doses of montelukast and seratrodast did not inhibit it. That study also demonstrated that inhaled KP-496 inhibited the immediate asthmatic response (IAR), late asthmatic response (LAR) and AHR, though no studies have presented findings concerning the anti-inflammatory effects of KP-496.…”

“…KP-496 [2-(N-[4-(4-chlorobenzenesulfonylamino)butyl]-N-[3-(4-isopropylthiazol-2-yl)methoxy]benzyl)sulfamoylbenzoic acid], a novel dual antagonist of cysLT receptor and TP, was synthesized by Kaken Pharmaceutical Co. Ltd. [23,24] and is currently in clinical development as a dry powder inhaler, KP-496DPI. The antagonistic activities of KP-496 for both LTD 4 and TXA 2 are comparable to the cysLT receptor antagonists and TP antagonist already launched [23] .…”

Enhanced airway smooth muscle cell thromboxane receptor signaling via activation of JNK MAPK and extracellular calcium influx

“…TXA 2 synthase inhibitors and TP receptor antagonists have been developed as anti-asthma drugs, and demonstrated to improve TP receptor-induced airflow limitation and bronchial hyperresponsiveness (Hanson et al, 2005;Ishimura et al, 2008;McKenniff et al, 1991). However, the signaling pathway responsible for modulation of TP receptor mediated airway hyperresponsiveness to TXA 2 is not clear.…”

Emerging drugs for asthma

“…However, some specific inhibitors, notably cysteinyl leukotriene antagonists, have had promising clinical effects. Moreover, a study that used sensitised guinea-pigs reported that the use of dual antagonists that target cysteinyl leukotriene receptor 1 and thromboxane α -2 receptors had significant effects on airway obstruction in this animal model, suggesting that such an approach may prove beneficial in asthma treatment [6] .…”