CJ-023,423, a novel, potent and selective prostaglandin EP4 receptor antagonist with antihyperalgesic properties.
The prostaglandin (PG) EP(4) receptor subtype is expressed by peripheral sensory neurons. Although a potential role of EP(4) receptor in pain has been suggested, a limited number of selective ligands have made it difficult to explore the physiological functions of EP(4) or its potential as a new analgesic target. Here, we describe the in vitro and in vivo pharmacology of a novel EP(4) 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 [(3)H]PGE(2) binding to both human and rat EP(4) receptors with K(i) of 13 +/- 4 and 20 +/- 1 nM, respectively. CJ-023,423 is highly selective for the human EP(4) receptor over other human prostanoid receptor subtypes. It also inhibits PGE(2)-evoked elevation in intracellular cAMP at the human and rat EP(4) receptors with pA(2) 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 PGE(2) (ED(50) = 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 EP(4) receptors, produces antihyperalgesic effects in animal models of inflammatory pain. Thus, specific blockade of the EP(4) receptor signaling may represent a novel therapeutic approach for the treatment of inflammatory pain.
Nakao
Kazunari
K
Discovery Biology Research, Nagoya Laboratories, Pfizer Global Research and Development, Pfizer Inc., 5-2 Taketoyo, Aichi, 470-2393, Japan. junji.takada@pfizer.com.
Murase
Akio
A
Ohshiro
Hiroyuki
H
Okumura
Takako
T
Taniguchi
Kana
K
Murata
Yoko
Y
Masuda
Masatoshi
M
Kato
Tomoki
T
Okumura
Yoshiyuki
Y
Takada
Junji
J
D000700:Analgesics / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D001667:Binding, Competitive; D002351:Carrageenan / Q000633:toxicity; D002460:Cell Line; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000378:metabolism; D015232:Dinoprostone / Q000378:metabolism / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005620:Freund's Adjuvant / Q000633:toxicity; D005727:Ganglia, Spinal / Q000166:cytology; D006801:Humans; D006930:Hyperalgesia / Q000139:chemically induced / Q000188:drug therapy* / Q000517:prevention & control; D008297:Male; D015394:Molecular Structure; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D010146:Pain / Q000139:chemically induced / Q000188:drug therapy; D017288:Pain Threshold / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D018078:Receptors, Prostaglandin E / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D058309:Receptors, Prostaglandin E, EP4 Subtype; D013449:Sulfonamides / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D013997:Time Factors; D014162:Transfection; D007093:Imidazoles; D011725:Pyridines; D013453:Sulfonylurea Compounds; D000096926:Benzenesulfonamides
D000700:Analgesics; D002351:Carrageenan; D000242:Cyclic AMP; D015232:Dinoprostone; D005620:Freund's Adjuvant; D018078:Receptors, Prostaglandin E; D058309:Receptors, Prostaglandin E, EP4 Subtype; D013449:Sulfonamides; C545650:PTGER4 protein, human; C545652:Ptger4 protein, rat; C522837:grapiprant; D007093:Imidazoles; D011725:Pyridines; D013453:Sulfonylurea Compounds; D000096926:Benzenesulfonamides