Target Validation Information
Target ID T18876
Target Name Prostaglandin E2 receptor, EP4 subtype
Target Type
Clinical Trial
Drug Potency against Target ONO-4819 Drug Info EC50 = 19 nM [552444]
3-(2-cinnamylphenyl)acrylic acid Drug Info Ki = 4400 nM [528393]
3-(2-(4-methoxycinnamyl)phenyl)acrylic acid Drug Info Ki = 6200 nM [528393]
3-(2-(naphthalen-2-ylmethyl)phenyl)acrylic acid Drug Info Ki = 13000 nM [528393]
3-(2-((E)-3-phenylprop-1-enyl)phenyl)acrylic acid Drug Info Ki = 4400 nM [528393]
FR-181157 Drug Info Ki = 1020 nM [527530]
8-aza-11-deoxyprostaglandin E1 Drug Info Ki = 4.5 nM [527306]
Action against Disease Model ONO-4819 Prostaglandin E(2) (PGE(2)) positively regulates bone resorption and formation mainly mediated through the EP(4) receptor, a subtype of PGE(2) receptors. ONO-4819, an EP(4) receptor-selective agonist, has been shown to increase bone vol uMe, density, and strength; however, the mechanism of these effects has yet to be fully elucidated. In vitro studies using the multipotent mesenchymal cell line C3H10T1/2 showed that ONO-4819 induced alkaline phosphatase (ALPase) activity and up-regulated the mRNA expression of ALPase and Osterix. In contrast, ONO-4819 reduced the mRNA expression of peroxisome proliferator-activated receptor ? (PPAR?) and inhibited adipocyte differentiation of C3H10T1/2 cells, which findings are consistent with the observation that the age-dependent increase in adipocyte n uMber in the bone marrow was significantly suppressed in the ONO-4819-treated animals. ONO-4819 also dose-dependently increased osteoclast-like cell formation in vitro, but the required concentrations were much higher than those to induce osteoblast differentiation. [553075] Drug Info
The Effect of Target Knockout, Knockdown or Genetic Variations Reduction of the antiproliferative effect of PGE2 in the mixed lymphocyte response; Ductus arteriosus fails to close after birth resulting in neonatal death; Decreased incidenceand severity; Decreased lipopolysaccharide induced bone resorption by osteoclasts; Decreased formation of aberrant crypt foci following treatment with azoxymethane [552444]
References
Ref 552444Up-regulation of lymphocytic cholinergic activity by ONO-4819, a selective prostaglandin EP4 receptor agonist, in MOLT-3 human leukemic T cells. Vascul Pharmacol. 2004 Mar;41(2):51-8.
Ref 528393Bioorg Med Chem Lett. 2006 Nov 1;16(21):5639-42. Epub 2006 Aug 22.Comparison between two classes of selective EP(3) antagonists and their biological activities.
Ref 553075Prostaglandin E(2) receptor EP(4)-selective agonist (ONO-4819) increases bone formation by modulating mesenchymal cell differentiation. Eur J Pharmacol. 2011 Jan 10;650(1):396-402. doi: 10.1016/j.ejphar.2010.10.021. Epub 2010 Oct 20.
Ref 528393Bioorg Med Chem Lett. 2006 Nov 1;16(21):5639-42. Epub 2006 Aug 22.Comparison between two classes of selective EP(3) antagonists and their biological activities.
Ref 528393Bioorg Med Chem Lett. 2006 Nov 1;16(21):5639-42. Epub 2006 Aug 22.Comparison between two classes of selective EP(3) antagonists and their biological activities.
Ref 528393Bioorg Med Chem Lett. 2006 Nov 1;16(21):5639-42. Epub 2006 Aug 22.Comparison between two classes of selective EP(3) antagonists and their biological activities.
Ref 527530J Med Chem. 2005 May 5;48(9):3103-6.Discovery of diphenyloxazole and Ndelta-Z-ornithine derivatives as highly potent and selective human prostaglandin EP(4) receptor antagonists.
Ref 527306J Med Chem. 2004 Dec 2;47(25):6124-7.Lactams as EP4 prostanoid receptor agonists. 3. Discovery of N-ethylbenzoic acid 2-pyrrolidinones as subtype selective agents.

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