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

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 Freund9s 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.