Pharmacology of AM211, a Potent and Selective Prostaglandin D2 Receptor Type 2 Antagonist That Is Active in Animal Models of Allergic Inflammation
| Autor: | Christopher Baccei, Jilly F. Evans, Daniel S. Lorrain, Yen Troung, Hutchinson John H, Peppi Prasit, Janice Darlington, Gretchen Bain, Brian Andrew Stearns, Christopher D. King, Catherine Lee, Karin J. Stebbins, Alex R. Broadhead, Angelina M. Santini, Pat Prodanovich |
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| Rok vydání: | 2011 |
| Předmět: |
Adult
Male Rhinitis Allergic Perennial Prostaglandin Antagonists Guinea Pigs Receptors Prostaglandin Prostaglandin Pharmacology Biology Allergic inflammation Rats Sprague-Dawley Guinea pig Mice Random Allocation chemistry.chemical_compound Dogs Hypersensitivity medicine Animals Humans Receptors Immunologic Receptor Phenylacetates Prostaglandin D2 receptor Methylurea Compounds Mice Inbred BALB C Antagonist Pneumonia Eosinophil Rats Disease Models Animal Basophil activation HEK293 Cells medicine.anatomical_structure chemistry Immunology Molecular Medicine Female Protein Binding |
| Zdroj: | Journal of Pharmacology and Experimental Therapeutics. 338:290-301 |
| ISSN: | 1521-0103 0022-3565 |
| DOI: | 10.1124/jpet.111.180430 |
| Popis: | The prostaglandin D(2) (PGD(2)) receptor type 2 (DP2) is a G protein-coupled receptor that has been shown to be involved in a variety of allergic diseases, including allergic rhinitis, asthma, and atopic dermatitis. In this study, we describe the preclinical pharmacological and pharmacokinetic properties of the small-molecule DP2 antagonist [2'-(3-benzyl-1-ethyl-ureidomethyl)-6-methoxy-4'-trifluoromethyl-biphenyl-3-yl]-acetic acid (AM211). We determine that AM211 has high affinity for human, mouse, rat, and guinea pig DP2 and it shows selectivity over other prostanoid receptors and enzymes. Antagonist activity of AM211 at the DP2 receptor was confirmed by inhibition of PGD(2)-stimulated guanosine 5'-O-[γ-thio]triphosphate binding to membranes expressing human DP2. A basophil activation assay and a whole-blood assay of eosinophil shape change were used to demonstrate the ability of AM211 to potently antagonize PGD(2)-stimulated functional responses in relevant human cells and in the context of a physiologically relevant environment. AM211 exhibits good oral bioavailability in rats and dogs and dose-dependently inhibits 13,14-dihydro-15-keto-PGD(2)-induced leukocytosis in a guinea pig pharmacodynamic assay. AM211 demonstrates efficacy in two animal models of allergic inflammation, including an ovalbumin-induced lung inflammation model in guinea pigs and an ovalbumin-induced mouse model of allergic rhinitis. AM211 represents a potent and selective antagonist of DP2 that may be used clinically to evaluate the role of DP2 in T helper 2-driven allergic inflammatory diseases. |
| Databáze: | OpenAIRE |
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