AM-211

The prostaglandin D2 receptor type 2 (DP2) and its ligand, PGD2, have been implicated in the development of asthma and other inflammatory diseases. The authors evaluated the pharmacodynamics, pharmacokinetics and safety of [2′‐(3‐benzyl‐1‐ethyl‐ureidomethyl)‐6‐methoxy‐4′‐ trifluoromethyl‐biphenyl‐3‐yl]‐acetic acid sodium salt (AM211), a novel and potent DP2 antagonist, in healthy participants. Single and multiple doses of AM211 demonstrated dose‐dependent inhibition of eosinophil shape change in blood with near‐complete inhibition observed at trough after dosing 200 mg once daily for 7 days. Maximum plasma concentrations and exposures of AM211 increased in a greater‐than‐dose‐proportional manner after single and multiple dosing. After multiple dosing, the exposures on day 7 were higher than on day 1 with accumulation ratio values ranging from 1.4 to 1.5. Mean terminal half‐life values ranged from 14 to 25 hours across the dose range of 100 to 600 mg. AM211 was well tolerated at all doses in both the single‐ and multiple‐dose cohorts. These data support additional clinical studies to evaluate AM211 in asthma and other inflammatory diseases.

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.