Description
Prostaglandin E
2 (PGE
2) activates four E prostanoid (EP) receptors, EP
1-4. EP
4 is a G
s protein-coupled receptor that, by elevating the second messenger cAMP, plays important roles in bone formation and resorption, cancer, and atherosclerosis. CJ-023423 is a potent and selective antagonist of the EP
4 receptor (K
i = 13 and 20 nM for human and rat EP
4, respectively). It inhibits PGE
2-evoked elevation in intracellular cAMP in cells and,
in vivo, reduces thermal hyperalgesia induced by intraplantar injection of PGE
2. CJ-023423 reduces acute and chronic inflammatory pain in different mouse models.
Uses
CJ-023423 is a potent and selective antagonist of E prostanoid 4 (EP4) receptor.
Biological Functions
Grapiprant (CJ-023423) is an orally available, a potent and selective EP4 receptor antagonist that exhibits significant inhibitory effects on paw swelling, inflammatory biomarkers, synovial inflammation and bone destruction in AIA rats. Grapiprant is highly selective for the human EP4 receptor over other human prostanoid receptor subtypes. It also inhibits PGE2-evoked elevation in intracellular cAMP at the human and rat EP4 receptors with pA2 of 8.3 and 8.2 nM, respectively. In vivo, oral administration of grapiprant significantly reduces thermal hyperalgesia induced by intraplantar injection of PGE2 (ED50 = 12.8 mg/kg). It is also effective in models of acute and chronic inflammatory pain. Grapiprant significantly reduces mechanical hyperalgesia in the carrageenan model. Furthermore, it significantly reverses complete Freund′s adjuvant-induced chronic inflammatory pain response. It produces antihyperalgesic effects in animal models of inflammatory pain. Grapiprant is approved and widely used for treatment of osteoarthritis related pain in dogs. Grapiprant is classify as a non-cyclooxygenase inhibiting non-steroidal anti-inflammatory drug (NSAID).
Side effects
Possible side effects of Grapiprant include: vomiting, drowsiness, diarrhoea, loss of appetite, blood or mucus in the stool, and reduced blood protein levels. The degree of reaction can vary from mild to severe, but if your dog experiences a loss of appetite or abnormal faeces, you should contact your veterinarian promptly.
in vitro
in vitro, cj-023,423 was able to inhibit [(3)h]pge(2) binding to both human and rat ep(4) receptors. cj-023,423 was found to be highly selective for the human ep(4) receptor over other human prostanoid receptor subtypes. cj-023,423 also inhibited pge(2)-evoked elevation in intracellular camp at the human and rat ep(4) receptors with pa(2) of 8.3 and 8.2 nm, respectively [1].
in vivo
in vivo, po administration of cj-023,423 could significantly reduce the thermal hyperalgesia that was induced by i.p. injection of pge(2). cj-023,423 was also effective in models of acute and chronic inflammatory pain. in addition, cj-023,423 was able to significantly reduce mechanical hyperalgesia in the carrageenan model. furthermore, cj-023,423 reversed complete freund's adjuvant-induced chronic inflammatory pain response significantly [1].
References
[1] KAZUNARI NAKAO. CJ-023,423, a novel, potent and selective prostaglandin EP4 receptor antagonist with antihyperalgesic properties.[J]. ACS Applied Electronic Materials, 2007: 686-694. DOI:
10.1124/jpet.107.122010[2] TAKAKO OKUMURA. Effects of the selective EP4 antagonist, CJ-023,423 on chronic inflammation and bone destruction in rat adjuvant-induced arthritis[J]. Journal of Pharmacy and Pharmacology, 2010, 60 6: 723-730. DOI:
10.1211/jpp.60.6.0007[3] Q CHEN. A novel antagonist of the prostaglandin E(2) EP(4) receptor inhibits Th1 differentiation and Th17 expansion and is orally active in arthritis models.[J]. British Journal of Pharmacology, 2010, 160 2: 292-310. DOI:
10.1111/j.1476-5381.2010.00647.x[4] DINGZHI WANG R D. The Role of Prostaglandin E(2) in Tumor-Associated Immunosuppression.[J]. Trends in molecular medicine, 2016, 22 1 1: 1-3. DOI:
10.1016/j.molmed.2015.11.003[5] NCT03696212 and NCT03658772
