Effect of prostanoid EP4 receptor antagonist, CJ-042,794, in rat models of pain and inflammation.
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.
Murase
Akio
A
Pfizer Global Research and Development, Pfizer Inc., Discovery Biology Research, Nagoya Laboratories, 5-2, Taketoyo, Aichi, 470-2393, Japan.
Okumura
Takako
T
Sakakibara
Ayano
A
Tonai-Kachi
Hiroko
H
Nakao
Kazunari
K
Takada
Junji
J
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
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