Grapiprant

Description

Prostaglandin E₂ (PGE₂) activates four E prostanoid (EP) receptors, EP_1-4. EP₄ 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 EP₄ receptor (K_i = 13 and 20 nM for human and rat EP₄, respectively). It inhibits PGE₂-evoked elevation in intracellular cAMP in cells and, in vivo, reduces thermal hyperalgesia induced by intraplantar injection of PGE₂. CJ-023423 reduces acute and chronic inflammatory pain in different mouse models.

The Uses of Grapiprant

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).

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) Nakao?et al.?(2007),?CJ-023,423, a novel, potent and selective prostaglandin EP4 receptor antagonist with antihyperalgesic properties;?J. Pharmacol. Exp. Ther.?332?686 2) Okumura?et al.?(2008),?Effects of the selective EP4 antagonist, CJ-023,423 on chronic inflammation and bone destruction in rat adjuvant-induced arthritis;?J. Pharm. Pharmacol.?60?7235 3) Chen?et al.?(2010),?A novel antagonist of the prostaglandin E2 EP4 receptor inhibits Th1 differentiation and Th17 expansion and is orally active in arthritis models;?Br. J. Pharmacol.?160?292 4) Wang and DuBois (2016),?Wang and DuBois (2016), The Role of Prostaglandin E2 in Tumor-Associated Immunosuppression;?Trends Mol. Med.?22?1 5) NCT03696212 and NCT03658772