Effect of the potent and selective DP1 receptor antagonist, asapiprant (S-555739), in animal models of allergic rhinitis and allergic asthma

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• 作者：Go Takahashi^a ; Fujio Asanuma^a ; Noriko Suzuki^b ; Maki Hattori^c ; Shingo Sakamoto^d ; Akira Kugimiya^b ; Yasuhiko Tomita^a ; Goro Kuwajima^e ; William M. Abraham^f ; Masashi Deguchi^g ; Akinori Arimura^e ; Michitaka Shichijo^a ; ^{michitaka.shichijou@shionogi.co.jp" class="auth_mail" title="E-mail the corresponding author}
• 关键词：AHR ; airway hyper-responsiveness ; AUC ; area under the curve ; BALF ; bronchoalveolar lavage fluid ; cAMP ; cyclic adenosine monophosphate ; CRTH2 ; chemoattractant receptor homologous molecule expressed on Th2 cells ; Cmax ; maximum concentration achieved after dosing ; IAR ; immediate airway response ; IC50 ; half-maximal inhibitory concentration ; Ki ; inhibitor constant ; LAR ; late airway response ; LT ; leukotriene ; OVA ; ovalbumin ; PC400 ; 400% increase in lung resistance ; PG ; prostaglandin ; RL ; lung resistan
• 刊名：European Journal of Pharmacology
• 出版年：2015
• 出版时间：15 October 2015
• 年：2015
• 卷：765
• 期：Complete
• 页码：15-23
• 全文大小：785 K

文摘

Prostaglandin (PG) D₂ elicits responses through either the DP₁ and/or DP₂ receptor. Experimental evidence suggests that stimulation of the DP₁ receptor contributes to allergic responses, such that antagonists are considered to be directed therapies for allergic diseases. In this study, we demonstrate the activity of a novel synthetic DP₁ receptor antagonist termed asapiprant (S-555739) for the DP₁ receptor and other receptors in vitro, and assess the efficacy of asapiprant in several animal models of allergic diseases. We determined the affinity and selectivity of asapiprant for the DP₁ receptor in binding assays. In the animal models of allergic rhinitis, changes in nasal resistance, nasal secretion, and cell infiltration in nasal mucosa were assessed after antigen challenge with and without asapiprant. Similarly, in the animal models of asthma, the effect of antigen challenge with and without asapiprant on antigen-induced bronchoconstriction, airway hyper-responsiveness, mucin production, and cell infiltration in lung were assessed. In binding studies, asapiprant exhibited high affinity and selectivity for the DP₁ receptor. Significant suppression of antigen-induced nasal resistance, nasal secretion, and cell infiltration in nasal mucosa was observed with asapiprant treatment. In addition, treatment with asapiprant suppressed antigen-induced asthmatic responses, airway hyper-responsiveness, and cell infiltration and mucin production in lung. These results show that asapiprant is a potent and selective DP₁ receptor antagonist, and exerts suppressive effects in the animal models of allergic diseases. Thus, asapiprant has potential as a novel therapy for allergic airway diseases.