title: Effect of prostanoid EP4 receptor antagonist, CJ-042,794, in rat models of pain and inflammation.
abstract: Recent study suggests that the proinflammatory and nociceptive effects of prostaglandin E(2) are mediated by prostanoid receptor subtype EP(4) and prostanoid EP(4) receptor may be a potential target for the treatment of inflammatory pain. Here we describe pharmacological characterization of a novel prostanoid EP(4) receptor antagonist, CJ-042,794 (4-{(1S)-1-[({5-chloro-2-[(4-fluorophenyl) oxy] phenyl} carbonyl) amino] ethyl} benzoic acid) in comparison with piroxicam (non-steroidal anti-inflammatory drug) or rofecoxib (cyclooxygenase-2 inhibitor). CJ-042,794 competitively antagonized cAMP accumulation with a pA(2) value of 8.7 in HEK293 cells overexpressing rat prostanoid EP(4) receptors. Orally administered CJ-042,794 dose-dependently inhibited carrageenan-induced mechanical hyperalgesia with an ED(50) value of 4.7 mg/kg (11 micromol/kg) and its maximal activity was somewhat less effective than that of 10 mg/kg piroxicam (30 micromol/kg p.o.). When CJ-042,794 and rofecoxib were administered to adjuvant-induced arthritis rats on Days 12-22 twice daily, both compounds reversed paw swelling to normal levels. These results suggest that a pharmacological blockade of the prostanoid EP(4) receptor may represent a new therapeutic strategy in signs and symptomatic relief of osteoarthritis and/or rheumatoid arthritis.
authors.affiliation: Pfizer Global Research and Development, Pfizer Inc., Discovery Biology Research, Nagoya Laboratories, 5-2, Taketoyo, Aichi, 470-2393, Japan.
authors.forename: Akio
authors.initials: A
authors.lastname: Murase
authors.forename: Takako
authors.initials: T
authors.lastname: Okumura
authors.forename: Ayano
authors.initials: A
authors.lastname: Sakakibara
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: D000284:Administration, Oral; D000700:Analgesics / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage / Q000494:pharmacology; D001549:Benzamides; D001565:Benzoates / Q000008:administration & dosage / Q000494:pharmacology*; D002460:Cell Line; D000242:Cyclic AMP / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D066298:In Vitro Techniques; D007249:Inflammation / Q000188:drug therapy*; D007783:Lactones / Q000494:pharmacology; D008297:Male; D010146:Pain / Q000188:drug therapy*; D010147:Pain Measurement; D010894:Piroxicam / Q000494:pharmacology; D051381:Rats; D011917:Rats, Inbred Lew; D018078:Receptors, Prostaglandin E / Q000037:antagonists & inhibitors*; D058309:Receptors, Prostaglandin E, EP4 Subtype; D013450:Sulfones / Q000494:pharmacology
chemical_list: C523467:(S)-4-(1-(5-chloro-2-(4-fluorophenyoxy) benzamido)ethyl) benzoic acid; D000700:Analgesics; D000893:Anti-Inflammatory Agents; D001549:Benzamides; D001565:Benzoates; D007783:Lactones; C545652:Ptger4 protein, rat; D018078:Receptors, Prostaglandin E; D058309:Receptors, Prostaglandin E, EP4 Subtype; D013450:Sulfones; C116926:rofecoxib; D010894:Piroxicam; D000242:Cyclic AMP