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First published on February 20, 2008; DOI: 10.1124/jpet.107.134510

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Received for publication December 17, 2007.
Revised February 12, 2008.
Accepted for publication February 19, 2008.

MF498, a selective EP4 antagonist, relieves joint inflammation and pain in rodent models of rheumatoid and osteoarthritis

Patsy Clark 1, Steven E Rowland 1, Danielle Denis 1, Marie-Claude Mathieu 1, Rino Stocco 1, Hugo Poirier 1, Jason Burch 1, Yongxin Han 1, Laurent Audoly 1, Alex G Therien 1, Daigen Xu 1*

1 Merck Frosst for Therapeutic Research

* Address correspondence to: E-mail: daigen_xu{at}merck.com

Abstract

Previous evidence has implicated EP4 in mechanical hyperalgesia induced by subplantar inflammation. However, its role in chronic arthritis remains to be further defined because previous attempts have generated two conflicting lines of evidence, with one showing a marked reduction of arthritis induced by a collagen antibody (CAIA) in mice lacking EP4 but not EP1-EP3, and the other showing no impact of EP4 antagonism on arthritis induced by collagen (CIA). Here, we assessed the effect of a novel and selective EP4 antagonist MF498 on inflammation in adjuvant-induced arthritis (AIA), a rat model for rheumatoid arthritis (RA), and joint pain in a guinea pig model of iodoacetate-induced osteoarthritis (OA). In the AIA model, MF498, but not the antagonist for EP1 MF266-1 or EP3 MF266-3, inhibited inflammation, with a similar efficacy as a selective COX-2 inhibitor MF-tricyclic. In addition, MF498 was as effective as an NSAID diclofenac or a selective mPGES-1 inhibitor MF63 in relieving OA-like pain in guinea pigs. When tested in rat models of gastrointestinal toxicity, the EP4 antagonist was well tolerated, causing no mucosal leakage or erosions. Lastly, we evaluated the renal effect of MF498 in a furosemide-induced diuresis model and demonstrated that the compound displayed a similar renal effect as a COX-2 inhibitor MF-tricyclic, reducing furosemide-induced natriuresis by ~50%. These results not only suggest that EP4 is the major EP receptor in both RA and OA but also provide a proof of principle to the concept that antagonism of EP4 may be useful for treatment of arthritis.


Key words: EP4, arthritis, diuresis, inflammation, pain, stomach


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D. Xu, S. E. Rowland, P. Clark, A. Giroux, B. Cote, S. Guiral, M. Salem, Y. Ducharme, R. W. Friesen, N. Methot, et al.
MF63 [2-(6-Chloro-1H-phenanthro[9,10-d]imidazol-2-yl)-isophthalonitrile], a Selective Microsomal Prostaglandin E Synthase-1 Inhibitor, Relieves Pyresis and Pain in Preclinical Models of Inflammation
J. Pharmacol. Exp. Ther., September 1, 2008; 326(3): 754 - 763.
[Abstract] [Full Text] [PDF]


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