Novel tricyclic antagonists of the prostaglandin D2 receptor DP2 with efficacy in a murine model of allergic rhinitis.
The synthesis of a series of tricyclic antagonists for the prostaglandin D(2) receptor DP2 (CRTH2) is disclosed. The activities of the compounds were evaluated in a human DP2 binding assay and a human whole blood eosinophil shape change assay. Potential metabolic liabilities of the compounds were addressed through in vitro CYP studies. The lead compound was demonstrated to have efficacy in a mouse model of allergic rhinitis following oral dosing.
Stearns
Brian A
BA
Amira Pharmaceuticals, San Diego, CA 92121, USA. brian.stearns@amirapharm.com
Baccei
Christopher
C
Bain
Gretchen
G
Broadhead
Alex
A
Clark
Ryan C
RC
Coate
Heather
H
Evans
Jilly F
JF
Fagan
Patrick
P
Hutchinson
John H
JH
King
Christopher
C
Lee
Catherine
C
Lorrain
Daniel S
DS
Prasit
Peppi
P
Prodanovich
Pat
P
Santini
Angelina
A
Scott
Jill M
JM
Stock
Nicholas S
NS
Truong
Yen P
YP
D000818:Animals; D018926:Anti-Allergic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D000893:Anti-Inflammatory Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D006575:Heterocyclic Compounds, 3-Ring / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D051379:Mice; D011971:Receptors, Immunologic / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011982:Receptors, Prostaglandin / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012221:Rhinitis, Allergic, Perennial / Q000188:drug therapy*
D018926:Anti-Allergic Agents; D000893:Anti-Inflammatory Agents; D006575:Heterocyclic Compounds, 3-Ring; D011971:Receptors, Immunologic; D011982:Receptors, Prostaglandin; D003577:Cytochrome P-450 Enzyme System; C036293:prostaglandin D2 receptor