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

Ishimura, Masakazu; Kataoka, Sayuri; Suda, Masashi; Maeda, Takashi; Hiyama, Yoshiyuki

doi:10.2332/allergolint.55.403

Cited by 9 publications

(7 citation statements)

References 24 publications

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“…Indeed, these have been shown to be effective when used either alone or in combination for suppressing antigen-induced bronchoconstriction in guinea pigs (Yoshimi et al, 2001). Other drugs have been developed with dual leukotriene D4 and TXA 2 receptor antagonism with efficacy in experimental models of allergic inflammation (Yamada et al, 2003;Ishimura et al, 2006). However, the efficacy of TXA 2 synthase inhibitors and receptor antagonists does not spread to all inflammatory diseases where activated platelets are a component.…”

Section: Antagonists Of Pleiotropic Mediators Released By Plateletsmentioning

confidence: 99%

Novel uses for anti‐platelet agents as anti‐inflammatory drugs

Pitchford

2007

British J Pharmacology

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An alteration in the character and function of platelets is manifested in patients with inflammatory diseases, and these alterations have been dissociated from the well‐characterized involvement of platelets in thrombosis and haemostasis. Recent evidence reveals platelet activation is sometimes critical in the development of inflammation. The mechanisms by which platelets participate in inflammation are diverse, and offer numerous opportunities for future drug intervention. There is now acceptance that platelets act as innate inflammatory cells in immune responses, with roles as sentinel cells undergoing surveillance, responding to microbial invasion, orchestrating leukocyte recruitment, and migrating through tissue, causing damage and influencing repair processes in chronic disease. Some of these processes are targeted by drugs that are being developed to target platelet participation in atherosclerosis. The actions of platelets therefore influence the pathogenesis of diverse inflammatory diseases in various body compartments, encompassing parasitic and bacterial infection, allergic inflammation (especially asthma and rhinitis), and non‐atopic inflammatory conditions, for example, chronic obstructive pulmonary disease (COPD), rheumatoid arthritis (RA), inflammatory bowel disease (IBD) and atherosclerosis. This review will first discuss the evidence for platelet activation in these various inflammatory diseases, and secondly discuss the mechanisms by which this pathogenesis occurs and the various anti‐platelet agents which have been developed to combat platelet activation in atherosclerosis and their potential future use for the treatment of other inflammatory diseases.British Journal of Pharmacology (2007) 152, 987–1002; doi:10.1038/sj.bjp.0707364; published online 2 July 2007

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Section: Antagonists Of Pleiotropic Mediators Released By Plateletsmentioning

confidence: 99%

Novel uses for anti‐platelet agents as anti‐inflammatory drugs

Pitchford

2007

British J Pharmacology

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“…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.…”

Section: Introductionmentioning

confidence: 58%

“…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] .…”

Section: Introductionmentioning

confidence: 99%

The Effects of Inhaled KP-496, a Novel Dual Antagonist for Cysteinyl Leukotriene Receptor and Thromboxane A<sub>2</sub> Receptor, on Allergic Asthmatic Responses in Guinea Pigs

et al. 2009

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Aims: The aim of this study was to evaluate the effects of inhaled KP-496, a novel dual antagonist for cysteinyl leukotriene receptor 1 and thromboxane A₂ receptor, on the allergic asthmatic responses in guinea pigs. Methods: Actively sensitized animals were repeatedly exposed to antigen, and KP-496 (0.01 and 0.1%) was inhaled for 5 min before every antigen exposure. After evaluating the effects of KP-496 on asthmatic responses, such as immediate and late asthmatic response (IAR and LAR) and airway hyperresponsiveness (AHR), histopathological analyses of the lungs of asthmatic animals were made. Results: KP-496 significantly inhibited both antigen-induced LAR and AHR to acetylcholine, and slightly inhibited antigen-induced IAR. Furthermore, histopathological analyses of the lungs of the asthmatic animals demonstrated the following: (1) KP-496 suppressed infiltration of eosinophils around airway smooth muscle, (2) KP-496 suppressed airway epithelial hypertrophy, and (3) KP-496 suppressed increased mucus production in the airway. Conclusion: In addition to suppression of LAR and AHR, our findings demonstrated that KP-496 inhibits features of airway inflammation. Since these broad ameliorative effects of KP-496 on asthmatic pathology are thought to result from the inhibition of multiple chemical mediators, KP-496 will be a potent agent in the treatment of bronchial asthma.

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“…In the LTD 4 -induced contraction of the trachea, the antagonistic activity of KP-496 was comparable to those of pranlukast and zafirlukast, and was stronger than that of montelukast. Furthermore, the antagonistic activity of KP-496 against the U-46619-induced tracheal contraction was comparable to that of seratrodast [14].…”

Section: Introductionmentioning

confidence: 63%

“…Research indicates that KP-496 is a dual antagonist for LTD 4 and TXA 2 receptors [14]. In an in vitro study using isolated guinea pig trachea, KP-496 produced parallel rightward shifts of both LTD 4 -and U-46619 (a TXA 2 mimetic)-induced contractions in a concentration-dependent manner.…”

Section: Introductionmentioning

confidence: 98%