title: In vitro pharmacological characterization of CJ-042794, a novel, potent, and selective prostaglandin EP(4) receptor antagonist.
abstract: Activation of the prostaglandin E(2) (PGE(2)) EP(4) receptor, a G-protein-coupled receptor (GPCR), results in increases in intracellular cyclic AMP (cAMP) levels via stimulation of adenylate cyclase. Here we describe the in vitro pharmacological characterization of a novel EP(4) receptor antagonist, CJ-042794 (4-{(1S)-1-[({5-chloro-2-[(4-fluorophenyl)oxy]phenyl}carbonyl)amino]ethyl}benzoic acid). CJ-042794 inhibited [(3)H]-PGE(2) binding to the human EP(4) receptor with a mean pK(i) of 8.5, a binding affinity that was at least 200-fold more selective for the human EP(4) receptor than other human EP receptor subtypes (EP(1), EP(2), and EP(3)). CJ-042794 did not exhibit any remarkable binding to 65 additional proteins, including GPCRs, enzymes, and ion channels, suggesting that CJ-042794 is highly selective for the EP(4) receptor. CJ-042794 competitively inhibited PGE(2)-evoked elevations of intracellular cAMP levels in HEK293 cells overexpressing human EP(4) receptor with a mean pA(2) value of 8.6. PGE(2) inhibited the lipopolysaccharide (LPS)-induced production of tumor necrosis factor alpha (TNFalpha) in human whole blood (HWB); CJ-042794 reversed the inhibitory effects of PGE(2) on LPS-induced TNFalpha production in a concentration-dependent manner. These results suggest that CJ-042794, a novel, potent, and selective EP(4) receptor antagonist, has excellent pharmacological properties that make it a useful tool for exploring the physiological role of EP(4) receptors.
authors.affiliation: Pfizer Global Research and Development, Discovery Biology Research, Aichi, Japan. Akio.Murase@pfizer.com
authors.forename: Akio
authors.initials: A
authors.lastname: Murase
authors.forename: Yasuhito
authors.initials: Y
authors.lastname: Taniguchi
authors.forename: Hiroko
authors.initials: H
authors.lastname: Tonai-Kachi
authors.forename: Kazunari
authors.initials: K
authors.lastname: Nakao
authors.forename: Junji
authors.initials: J
authors.lastname: Takada
mesh_terms: D000700:Analgesics / Q000494:pharmacology*; D001549:Benzamides; D001565:Benzoates / Q000494:pharmacology*; D001665:Binding Sites; D001667:Binding, Competitive; D002460:Cell Line; D000242:Cyclic AMP / Q000037:antagonists & inhibitors / Q000378:metabolism; D015232:Dinoprostone / Q000378:metabolism* / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004847:Epithelial Cells / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D007668:Kidney / Q000196:embryology; D008070:Lipopolysaccharides / Q000494:pharmacology; D011485:Protein Binding; D018078:Receptors, Prostaglandin E / Q000037:antagonists & inhibitors* / Q000378:metabolism; D058309:Receptors, Prostaglandin E, EP4 Subtype; D014409:Tumor Necrosis Factor-alpha / Q000097:blood
chemical_list: C523467:(S)-4-(1-(5-chloro-2-(4-fluorophenyoxy) benzamido)ethyl) benzoic acid; D000700:Analgesics; D001549:Benzamides; D001565:Benzoates; D008070:Lipopolysaccharides; C545650:PTGER4 protein, human; D018078:Receptors, Prostaglandin E; D058309:Receptors, Prostaglandin E, EP4 Subtype; D014409:Tumor Necrosis Factor-alpha; D000242:Cyclic AMP; D015232:Dinoprostone