title: Pharmacology of AM211, a potent and selective prostaglandin D2 receptor type 2 antagonist that is active in animal models of allergic inflammation.
abstract: 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.
authors.affiliation: Amira Pharmaceuticals, San Diego, California 92121, USA. gretchen.bain@amirapharm.com
authors.forename: Gretchen
authors.initials: G
authors.lastname: Bain
authors.forename: Daniel S
authors.initials: DS
authors.lastname: Lorrain
authors.forename: Karin J
authors.initials: KJ
authors.lastname: Stebbins
authors.forename: Alex R
authors.initials: AR
authors.lastname: Broadhead
authors.forename: Angelina M
authors.initials: AM
authors.lastname: Santini
authors.forename: Pat
authors.initials: P
authors.lastname: Prodanovich
authors.forename: Janice
authors.initials: J
authors.lastname: Darlington
authors.forename: Christopher D
authors.initials: CD
authors.lastname: King
authors.forename: Catherine
authors.initials: C
authors.lastname: Lee
authors.forename: Christopher
authors.initials: C
authors.lastname: Baccei
authors.forename: Brian
authors.initials: B
authors.lastname: Stearns
authors.forename: Yen
authors.initials: Y
authors.lastname: Troung
authors.forename: John H
authors.initials: JH
authors.lastname: Hutchinson
authors.forename: Peppi
authors.initials: P
authors.lastname: Prasit
authors.forename: Jilly F
authors.initials: JF
authors.lastname: Evans
mesh_terms: D000328:Adult; D000818:Animals; D004195:Disease Models, Animal; D004285:Dogs; D005260:Female; D006168:Guinea Pigs; D057809:HEK293 Cells; D006801:Humans; D006967:Hypersensitivity / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism; D008297:Male; D008782:Methylurea Compounds / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D051379:Mice; D008807:Mice, Inbred BALB C; D010648:Phenylacetates / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D011014:Pneumonia / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism; D011448:Prostaglandin Antagonists / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D011485:Protein Binding / Q000502:physiology; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D011971:Receptors, Immunologic / Q000037:antagonists & inhibitors* / Q000276:immunology / Q000378:metabolism; D011982:Receptors, Prostaglandin / Q000037:antagonists & inhibitors* / Q000276:immunology / Q000378:metabolism; D012221:Rhinitis, Allergic, Perennial / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism
chemical_list: C560624:(2'-(3-benzyl-1-ethylureidomethyl)-6-methoxy-4'-trifluoromethylbiphenyl-3-yl)acetic acid; D008782:Methylurea Compounds; D010648:Phenylacetates; D011448:Prostaglandin Antagonists; D011971:Receptors, Immunologic; D011982:Receptors, Prostaglandin; C036293:prostaglandin D2 receptor