Session Type: ACR Poster Session A
Session Time: 9:00AM-11:00AM
Background/Purpose: Prostaglandin (PG) E2 is known to enhance the expansion of T helper 17 (Th17) cell population via EP4 receptor (EP4) in the early phase of rheumatoid arthritis (RA). Furthermore, EP4 signals are involved in inflammatory hyperalgesia. Therefore, EP4 antagonists would be useful disease modified anti-rheumatic drugs (DMARDs) with analgesic effect. On the basis of this concept, pharmacological characteristics of S-110483, our novel potent and selective EP4 antagonist, were compared with existing EP4 antagonists; in addition, evidence regarding the immunomodulatory/analgesic potential of S-110483 is provided using an RA model.
Methods: The antagonistic activities of S-110483 and existing EP4 antagonists were evaluated in mammalian cells overexpressing rat, mouse, or human EP4. The effects of S-110483 on the production of PGE2 and PGI2 were evaluated using human umbilical vein endothelial cells (HUVEC) stimulated with IL-1β. For estimating the effects on the Th17 expansion, inhibition of IL-23 release from mouse dendritic cells was measured. The anti-edema and analgesic effects of S-110483 were evaluated by using rat adjuvant-induced arthritis (AIA) models as follows. Rats received intradermal injections of adjuvant suspension on their left hind paw (day 0). S-110483 (0.003–3 mg/kg) or celecoxib (0.003–3 mg/kg) were orally administered once a day on days 9–20. On day 18, anti-hyperalgesia effects were evaluated by measuring the vocalization threshold. Anti-edema effects were evaluated by paw volume of day 8, day 14, and day 18.
Results: S-110483 showed potent antagonistic activities for the rat/mouse/human EP4 with IC50 of 10.9/9.0/5.4 nmol/L, respectively. S-110483 (10–1000 nmol/L) did not inhibit PGE2 and PGI2 production from HUVEC. S-110483 dose-dependently inhibited IL-23 release from activated mouse dendritic cells. The in vitro evaluation including the EP4 antagonistic activity revealed that S-110483 is the most potent and effective antagonist among existing EP4 antagonists. In the AIA models, S-110483 (0.3 mg/kg) had considerable analgesic and anti-inflammatory effects. Compared to celecoxib, S-110483 showed the maximum anti-hyperalgesic effects starting at dose that was 10 times lower.
Conclusion: Our studies demonstrated that S-110483 is the best in class among EP4 receptor antagonists, and it shows not only immunomodulatory effects but also anti-inflammatory and analgesic effects without inhibiting PGE2 and PGI2 production. These findings suggested that S-110483 could become a superior therapeutic option in RA patients.
To cite this abstract in AMA style:Maeda T, Ochiai T, Nagayasu-Tanaka T, Morisaki Y, Takizawa H, Ishihara S, Kurokawa S, Ukai K, Suda M. S-110483 a New Potent EP4 Receptor Antagonist with Immunomodulatory and Analgesic Activities [abstract]. Arthritis Rheumatol. 2017; 69 (suppl 10). https://acrabstracts.org/abstract/s-110483-a-new-potent-ep4-receptor-antagonist-with-immunomodulatory-and-analgesic-activities/. Accessed May 19, 2019.
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/s-110483-a-new-potent-ep4-receptor-antagonist-with-immunomodulatory-and-analgesic-activities/