Effects of KP-496, a Novel Dual Antagonist for Cysteinyl Leukotriene Receptor 1 and Thromboxane A2 Receptor, on Sephadex-Induced Airway Inflammation in Rats

Abstract

Bronchial asthma is characterized by chronic airway inflammation. Eosinophils are involved in airway inflammation and play crucial roles in asthma. There is accumulating evidence to suggest contributions of cysteinyl leukotrienes (cysLTs) and thromboxane (TX) A(2) to the recruitment of eosinophils into lung in asthmatics. KP-496 is a novel dual antagonist for CysLT receptor type 1 and TXA(2) receptors. The aim of this study was to evaluate the anti-inflammatory effects of KP-496 on Sephadex-induced airway inflammation. Sephadex suspension was intratracheally injected into rats. Amounts of regulated on activation, normal T cell expressed and secreted (RANTES) and eotaxin, and numbers of infiltrating cells in bronchoalveolar lavage fluid were measured 24 and 48 h after Sephadex injection, respectively. KP-496 (30, 100 microg/head) was intratracheally administered to rats 1 h before and 7 h after Sephadex injection. KP-496 and prednisolone (10 mg/kg, per os) exhibited significant inhibitory effects on infiltration of total cells and eosinophils into lung. Production of RANTES was significantly inhibited by KP-496 and prednisolone. Production of eotaxin was significantly inhibited by prednisolone. KP-496 also inhibited the production of eotaxin, though this effect was not significant. These results demonstrate that KP-496 exhibited the anti-inflammatory effects by inhibiting infiltration of inflammatory cells and productions of RANTES and eotaxin.

International Union of Basic and Clinical Pharmacology. LXXXIII: Classification of Prostanoid Receptors, Updating 15 Years of Progress

“…More recently, compounds with dual antagonist properties have been designed. For example, (2-(N-(4-(4-chlorobenzenesulfonylamino)butyl)-N-(3-(4-isopropylthiazol-2-yl)methoxy)benzyl)sulfamoyl)benzoic acid (KP-496) (Mizutani et al, 2008;Ishimura et al, 2009) and YM-158 (Fig. 11) (Arakida et al, 1998) are dual TP/cysteinyl leukotriene antagonists.…”

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

“…The relationship between respiratory function and increase in inflammatory cells in BALF is thus still controversial. It was not clear why only 0.01% KP-496 increased inflammatory cells in BALF, but we think this result might not be a risk in clinical studies for the following reasons: (1) as shown in this study, the increase in inflammatory cells in BALF did not correlate with changes in respiratory function or histopathology, and (2) intratracheally administered KP-496 significantly inhibited Sephadex-induced airway hypereosinophilia [35] , which is known to be associated with AHR [36] .…”

JTE-852, a novel spleen tyrosine kinase inhibitor, blocks antigen-induced allergic reactions in rats

“…We therefore selected the doses of ketotifen, pranlukast, and prednisolone at which they can fully perform their mechanisms of action, histamine antagonism, LTC 4 /D 4 /E 4 antagonism, and anti-inflammatory effects, respectively. From our background data and other previous reports, the doses were all 30 mg/kg [ 9 , 11 , 14 , 15 , 24 ]. The suppressive effects of the four articles included in this study are summarized in Table 1…”