Effects of KP-496, a novel dual antagonist of leukotriene D4 and thromboxane A2 receptors on nasal blockage in guinea pig models of allergic rhinitis

Mizutani, Nobuaki; Suda, Masashi; Ishimura, Masakazu; Kurokawa, Shigeo; Nabe, Takeshi; Kohno, Shigekatsu

doi:10.1007/s00011-007-7067-5

Cited by 3 publications

(2 citation statements)

References 22 publications

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“…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.…”

mentioning

confidence: 99%

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

Woodward

Jones

Narumiya³

2011

Pharmacol Rev

393

414

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mentioning

confidence: 99%

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

Woodward

Jones

Narumiya³

2011

Pharmacol Rev

393

414

View full text Add to dashboard Cite

“…7) [27]. In contrast, the inhibitory effect of KP‐496, a novel dual antagonist of LTD 4 and TXA 2 receptors, on the nasal blockage in guinea‐pig models of AR was greater than that of pranlukast [28]. Combined intra‐nasal instillation of LTD 4 and U‐46619 produced a much greater nasal blockage than an administration of either agonist alone in sensitized guinea‐pigs [22].…”

Section: Introductionmentioning

confidence: 99%

Mechanism of nasal obstruction in patients with allergic rhinitis

Ichimura

2010

Clin Exp All Rev

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Summary Nasal obstruction is a crucial symptom in allergic rhinitis (AR) patients and may affect the quality of life. It is caused mostly by nasal mucosal obstruction, and to a lesser extent, fluid secretion. Mucosal congestion is primarily a vascular phenomenon comprising vasodilatation of capacitance vessels (cavernous sinus) and oedema formation due to plasma leakage from post‐capillary venules. The nose has a complex microvascular anatomy consisting of capacitance vessels, arteriovenous anastomosis, and subepithelial and periglandular capillaries. Nasal congestion is explained by the effects of local mediators exerting potent vasodilatation or increasing permeability of nasal blood vessels and nerves. Capacitance vessels usually constrict because of constant sympathetic tone. They distend by a variety of stimuli such as loss of continuous sympathetic stimulation on the sinusoids, direct vasodilatation by vasoactive substances, contraction of cushion veins, and compression of venules by distended arteries in the intraosseous bony canals of periosteal space. Although topical application of histamine can cause vasodilatation and oedema, histamine is not likely a major mediator causative of nasal congestion in AR. Nasal vascular dilatation elicited by cysleukotriene 1 (cysLT1) may be induced by nitric oxide produced through cysLT1 receptor activation. Thromboxane A2 may cause capacitance vessel dilatation through a contraction of cushion veins. Potentiation of vasoconstrictor action of steroids has been reported since the 1950s. Glucocorticoids (GCs) have two fundamentally different vascular effects: classic action modifying the transcription of pro‐inflammatory genes and acute non‐genomic action (within minutes) that increases the vasomotor tone. The non‐genomic effect is likely related to binding of GCs to the plasma membrane and inhibition of extraneuronal monoamine transporter on vascular smooth muscle cells, thereby increasing noradrenaline concentrations at α1‐adrenoceptors. Genomic vascular effects include the reduction of vessel density, decrease of hyperperfusion, reduction of inflammatory microvascular hyperpermeability, and decreased influx and activation of inflammatory cells. These effects require hours to manifest themselves physiologically.

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Effect of inhaled KP-496, a novel dual antagonist of the cysteinyl leukotriene and thromboxane A2 receptors, on a bleomycin-induced pulmonary fibrosis model in mice

Kurokawa¹,

Suda²,

Okuda³

et al. 2010

Pulmonary Pharmacology & Therapeutics

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Effects of KP-496, a novel dual antagonist of leukotriene D4 and thromboxane A2 receptors on nasal blockage in guinea pig models of allergic rhinitis

Abstract: KP-496 may be clinically effective for nasal blockage in allergic rhinitis.

Cited by 3 publications

References 22 publications

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

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

Mechanism of nasal obstruction in patients with allergic rhinitis

Effect of inhaled KP-496, a novel dual antagonist of the cysteinyl leukotriene and thromboxane A2 receptors, on a bleomycin-induced pulmonary fibrosis model in mice

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