Therapeutic efficacy of AM156, a novel prostanoid DP2 receptor antagonist, in murine models of allergic rhinitis and house dust mite-induced pulmonary inflammation.
Prostaglandin D(2) (PGD(2)) is derived from arachidonic acid and binds with high affinity to the G protein coupled receptors prostanoid DP(1) and DP(2). Interaction with DP(2) results in cell chemotaxis, eosinophil degranulation, eosinophil shape change, adhesion molecule upregulation and Th2 cytokine production. In allergic rhinitis and allergic asthma PGD(2) is released from mast cells in response to allergen challenge and may trigger symptoms such as sneezing, rhinorrhea, pruritus, mucus hypersecretion and pulmonary inflammation. In Japan, ramatroban, a dual prostanoid DP(2)/prostanoid TP receptor antagonist, is marketed for allergic rhinitis while selective DP(2) antagonists are currently under investigation as therapeutics for asthma and allergic rhinitis. In the studies described herein, we investigated the efficacy of AM156, a novel selective prostanoid DP(2) receptor antagonist, in murine models of allergic rhinitis and asthma. AM156 inhibited sneezing and nasal rubs in a model of allergic rhinitis. AM156 inhibited pulmonary inflammation and mucus hypersecretion induced by chronic inhalation of house dust mite. These results suggest that selective prostanoid DP(2) receptor antagonists such as AM156 may provide beneficial effects for the clinical treatment of diseases such as allergic rhinitis and asthma.
Stebbins
Karin J
KJ
Amira Pharmaceuticals, 9535 Waples St., Ste. 100 San Diego, CA 92121, USA. karin.stebbins@amirapharm.com
Broadhead
Alex R
AR
Correa
Lucia D
LD
Scott
Jill M
JM
Truong
Yen P
YP
Stearns
Brian A
BA
Hutchinson
John H
JH
Prasit
Peppi
P
Evans
Jilly F
JF
Lorrain
Daniel S
DS
D000818:Animals; D018926:Anti-Allergic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D001249:Asthma / Q000188:drug therapy*; D001596:Benzylamines / Q000494:pharmacology / Q000627:therapeutic use*; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology / Q000276:immunology; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D007073:Immunoglobulin E / Q000097:blood; D008168:Lung / Q000276:immunology / Q000473:pathology*; D008679:Metaplasia / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D009077:Mucins / Q000378:metabolism; D011014:Pneumonia / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism; D039981:Pyroglyphidae / Q000276:immunology*; D011971:Receptors, Immunologic / Q000037:antagonists & inhibitors*; D011982:Receptors, Prostaglandin / Q000037:antagonists & inhibitors*; D012221:Rhinitis, Allergic, Perennial / Q000188:drug therapy* / Q000378:metabolism; D001713:Biphenyl Compounds
D018926:Anti-Allergic Agents; D001596:Benzylamines; D016207:Cytokines; D007073:Immunoglobulin E; D009077:Mucins; D011971:Receptors, Immunologic; D011982:Receptors, Prostaglandin; C548542:(2'-((cyclopropanecarbonylethylamino)methyl)-6-methoxy-4'-trifluoromethyl-biphenyl-3-yl)acetic acid; D001713:Biphenyl Compounds; C036293:prostaglandin D2 receptor