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NEUROPHARMACOLOGY

CJ-023,423, a Novel, Potent and Selective Prostaglandin EP₄ Receptor Antagonist with Antihyperalgesic Properties

Discovery Biology Research (A.M., H.O., T.O., K.T., Y.M., J.T.), Pharmacokinetics, Dynamics, and Metabolism (M.M.), and Discovery Chemistry Research (K.N., T.K., Y.O.), Pfizer Global Research and Development, Aichi, Japan

The prostaglandin (PG) EP₄ receptor subtype is expressed by peripheral sensory neurons. Although a potential role of EP₄ receptor in pain has been suggested, a limited number of selective ligands have made it difficult to explore the physiological functions of EP₄ or its potential as a new analgesic target. Here, we describe the in vitro and in vivo pharmacology of a novel EP₄ receptor antagonist, N-[({2-[4-(2-ethyl-4,6-dimethyl-1H-imidazo [4,5-c] pyridin-1-yl) phenyl]ethyl}amino) carbonyl]-4-methylbenzenesulfonamide (CJ-023,423). In vitro, CJ-023,423 inhibits [³H]PGE₂ binding to both human and rat EP₄ receptors with K_i of 13 ± 4 and 20 ± 1 nM, respectively. CJ-023,423 is highly selective for the human EP₄ receptor over other human prostanoid receptor subtypes. It also inhibits PGE₂-evoked elevation in intracellular cAMP at the human and rat EP₄ receptors with pA₂ of 8.3 ± 0.03 and 8.2 ± 0.2 nM, respectively. In vivo, oral administration of CJ-023,423 significantly reduces thermal hyperalgesia induced by intraplantar injection of PGE₂ (ED₅₀ = 12.8 mg/kg). CJ-023,423 is also effective in models of acute and chronic inflammatory pain. CJ-023,423 significantly reduces mechanical hyperalgesia in the carrageenan model. Furthermore, CJ-023,423 significantly reverses complete Freund's adjuvant-induced chronic inflammatory pain response. Taken together, the present data indicate that CJ-023,423, a highly potent and selective antagonist of both human and rat EP₄ receptors, produces antihyperalgesic effects in animal models of inflammatory pain. Thus, specific blockade of the EP₄ receptor signaling may represent a novel therapeutic approach for the treatment of inflammatory pain.

Address correspondence to: Dr. Junji Takada, Discovery Biology Research, Nagoya Laboratories, Pfizer Global Research and Development, Pfizer Inc., 5-2 Taketoyo, Aichi, 470-2393, Japan. E-mail: junji.takada{at}pfizer.com

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