Effect of the potent and selective DP1 receptor antagonist, asapiprant (S-555739), in animal models of allergic rhinitis and allergic asthma.
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.
Discovery Research Laboratory for Innovative Frontier Medicines, Shionogi & Co., Ltd., Toyonaka, Osaka, Japan.
Go
G
Takahashi
Discovery Research Laboratory for Innovative Frontier Medicines, Shionogi & Co., Ltd., Toyonaka, Osaka, Japan.
Fujio
F
Asanuma
Discovery Research Laboratory for Core Therapeutic Areas, Shionogi & Co., Ltd., Toyonaka, Osaka, Japan.
Noriko
N
Suzuki
Research Technology Services, Shionogi Techno Advance Research, Toyonaka, Osaka, Japan.
Maki
M
Hattori
Research Laboratory for Development, Shionogi & Co., Ltd., Toyonaka, Osaka, Japan.
Shingo
S
Sakamoto
Discovery Research Laboratory for Core Therapeutic Areas, Shionogi & Co., Ltd., Toyonaka, Osaka, Japan.
Akira
A
Kugimiya
Discovery Research Laboratory for Innovative Frontier Medicines, Shionogi & Co., Ltd., Toyonaka, Osaka, Japan.
Yasuhiko
Y
Tomita
Global Project Management, Shionogi & Co., Ltd., Osaka, Japan.
Goro
G
Kuwajima
Department of Research, Mount Sinai Medical Center, Miami Beach, FL 33140, USA.
William M
WM
Abraham
Strategic Research Planning Offices, Pharmaceutical Research Division, Shionogi & Co., Ltd., Toyonaka, Osaka, Japan.
Masashi
M
Deguchi
Global Project Management, Shionogi & Co., Ltd., Osaka, Japan.
Akinori
A
Arimura
Discovery Research Laboratory for Innovative Frontier Medicines, Shionogi & Co., Ltd., Toyonaka, Osaka, Japan. Electronic address: michitaka.shichijou@shionogi.co.jp.
Michitaka
M
Shichijo
D000818:Animals; D001249:Asthma / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism; D004195:Disease Models, Animal; D004285:Dogs; D005260:Female; D006168:Guinea Pigs; D006801:Humans; D008297:Male; D011453:Prostaglandins / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D051381:Rats; D011914:Rats, Inbred BN; D011982:Receptors, Prostaglandin / Q000037:antagonists & inhibitors* / Q000502:physiology; D012130:Respiratory Hypersensitivity / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism; D065631:Rhinitis, Allergic / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism; D012756:Sheep; D013876:Thiophenes / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D016896:Treatment Outcome
C432167:7(2-(5-hydroxybenzo(b)thiophen-3-ylcarbonylamino)-10-norpinan-3-yl)hept-5-enoic acid; D011453:Prostaglandins; D011982:Receptors, Prostaglandin; D013876:Thiophenes; C501562:prostanoid D receptor 1, human
Allergic rhinitis; Asapiprant; Nasal congestion; Prostaglandin D(2); Synthetic DP(1) receptor antagonist