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 E2 are mediated by prostanoid receptor subtype EP4 and prostanoid EP4 receptor may be a potential target for the treatment of inflammatory pain. Here we describe pharmacological characterization of a novel prostanoid EP4 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 pA2 value of 8.7 in HEK293 cells overexpressing rat prostanoid EP4 receptors. Orally administered CJ-042,794 dose-dependently inhibited carrageenan-induced mechanical hyperalgesia with an ED50 value of 4.7 mg/kg (11 μmol/kg) and its maximal activity was somewhat less effective than that of 10 mg/kg piroxicam (30 μmol/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 EP4 receptor may represent a new therapeutic strategy in signs and symptomatic relief of osteoarthritis and/or rheumatoid arthritis.