Effects of the selective EP4 antagonist, CJ-023,423 on chronic inflammation and bone destruction in rat adjuvant-induced arthritis.
Prostaglandin E2 (PGE2) produced by cyclooxygenase (COX) is a potent pro-inflammatory mediator. We have recently discovered CJ-023,423, a highly selective antagonist of EP4 receptors, one of the PGE2 receptors. This agent is suitable for exploring the effects of blocking EP4 receptors following oral administration in rats. In this study, CJ-023,423 was used in rats with adjuvant-induced arthritis (AIA) to investigate the role of the EP4 receptor in chronic inflammation and bone destruction. These effects were compared with those of rofecoxib, a selective COX-2 inhibitor. CJ-023,423 had significant inhibitory effects on paw swelling, inflammatory biomarkers, synovial inflammation and bone destruction in AIA rats. In particular, the inhibitory effect on paw swelling in AIA rats was comparable to that of rofecoxib. These results suggest that PGE2 acting via the EP4 receptor is involved in the development of chronic inflammation and bone destruction, particularly with respect to oedema in AIA rats. This is the first study to confirm the in-vivo effects of EP4 receptor blockade on inflammation and bone destruction in AIA rats with a small-molecule compound.
Okumura
Takako
T
Discovery Biology Research, Nagoya Laboratories, Pfizer Global Research and Development, Pfizer Inc., 5-2 Taketoyo, Aichi, 470-2393, Japan. Takako.Okumura@pfizer.com
Murata
Yoko
Y
Taniguchi
Kana
K
Murase
Akio
A
Nii
Aisuke
A
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage / Q000494:pharmacology*; D001169:Arthritis, Experimental / Q000188:drug therapy* / Q000503:physiopathology; D001862:Bone Resorption / Q000188:drug therapy / Q000209:etiology; D015232:Dinoprostone / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004487:Edema / Q000188:drug therapy / Q000209:etiology; D007249:Inflammation / Q000188:drug therapy / Q000209:etiology; D007783:Lactones / Q000494:pharmacology; D008297:Male; D051381:Rats; D011917:Rats, Inbred Lew; D018078:Receptors, Prostaglandin E / Q000037:antagonists & inhibitors*; D058309:Receptors, Prostaglandin E, EP4 Subtype; D013449:Sulfonamides / Q000008:administration & dosage / Q000494:pharmacology*; D013450:Sulfones / Q000494:pharmacology; D007093:Imidazoles; D011725:Pyridines; D013453:Sulfonylurea Compounds; D000096926:Benzenesulfonamides
D000893:Anti-Inflammatory Agents; D015232:Dinoprostone; D007783:Lactones; D018078:Receptors, Prostaglandin E; D058309:Receptors, Prostaglandin E, EP4 Subtype; D013449:Sulfonamides; D013450:Sulfones; C545652:Ptger4 protein, rat; C116926:rofecoxib; C522837:grapiprant; D007093:Imidazoles; D011725:Pyridines; D013453:Sulfonylurea Compounds; D000096926:Benzenesulfonamides