The DP2 receptor 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, AM211. We determine that AM211 has high affinity for human, mouse, rat and guinea pig DP2 and that it shows selectivity over other prostanoid receptors and enzymes. Antagonist activity of AM211 at the DP2 receptor was confirmed by inhibition of PGD2-stimulated GTPγS 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 PGD2-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 DK-PGD2-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 the DP2 receptor in Th2-driven allergic inflammatory diseases.
- Received February 10, 2011.
- Revision received April 6, 2011.
- Accepted April 8, 2011.
- The American Society for Pharmacology and Experimental Therapeutics