The discovery of 6-[2-(5-chloro-2-{[(2,4-difluorophenyl)methyl]oxy}phenyl)-1-cyclopenten-1-yl]-2-pyridinecarboxylic acid, GW848687X, a potent and selective prostaglandin EP1 receptor antagonist for the treatment of inflammatory pain

Giblin, Gerard M.P.; Bit, Rino A.; Brown, Susan H.; Chaignot, Helene M.; Chowdhury, Ashim; Chessell, Iain P.; Clayton, Nick M.; Coleman, Tanya; Hall, Adrian; Hammond, Beverley; Hurst, David N.; Michel, Anton D.; Naylor, Alan; Novelli, Riccardo; Scoccitti, Tiziana; Spalding, David J.; Tang, Sac P.; Wilson, Alex W.; Wilson, Rich

doi:10.1016/j.bmcl.2006.10.041

Cited by 42 publications

(14 citation statements)

References 33 publications

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“…These properties are generally similar or superior to those of similar compounds reported in the literature. Specifically, MF266-1 is more selective toward TP (60-fold) than the EP1 antagonist GW848687 (30-fold) (Giblin et al, 2007); MF266-3 shows better selectivity over EP4 (Ͼ7000-fold) than that of the reported EP3 receptor antagonist ONO-AE3-240 (250-fold with a K i for EP4 ϭ 58 nM) (Amano et al, 2003); and MF498 has a higher affinity for the EP4 receptor (0.7 versus 13 nM) and better bioavailability than CJ-023,423 (100 versus 4.6%) (Nakao et al, 2007). Furthermore, the antagonists used in the present study also have the desired potency and pharmacokinetic properties in rats and hence are suitable for studying the role of the target receptors in the rat AIA model.…”

Section: Discussionmentioning

confidence: 99%

MF498 [N-{[4-(5,9-Diethoxy-6-oxo-6,8-dihydro-7H-pyrrolo[3,4-g]quinolin-7-yl)-3-methylbenzyl]sulfonyl}-2-(2-methoxyphenyl)acetamide], a Selective E Prostanoid Receptor 4 Antagonist, Relieves Joint Inflammation and Pain in Rodent Models of Rheumatoid and Osteoarthritis

Clark¹,

Rowland²,

Denis³

et al. 2008

J Pharmacol Exp Ther

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Previous evidence has implicated E prostanoid receptor 4 (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 in mice lacking EP4, but not EP1-EP3, and the other showing no impact of EP4 antagonism on arthritis induced by collagen. Here, we assessed the effect of a novel and selective EP4 antagonist MF498 [N-{[4-(5,9-diethoxy-6-oxo-6,8-dihydro-7H-pyrrolo[3,4-g]quinolin-7-yl)-3-methylbenzyl]sulfonyl}-2-(2-methoxyphenyl)acetamide] 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,, inhibited inflammation, with a similar efficacy as a selective cyclooxygenase 2 (COX-2) inhibitor MF-tricyclic. In addition, MF498 was as effective as an nonsteroidal anti-inflammatory drug, diclofenac, or a selective microsomal prostaglandin E synthase-1 inhibitor, MF63 [2-(6-chloro-1H-phenanthro[9,10-d]imidazol-2-yl)isophthalonitrile], 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 MF-tricyclic [3-(3,4-difluorophenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone], reducing furosemideinduced natriuresis by ϳ50%. 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.Chronic joint inflammation and pain are the two main symptoms in patients with arthritis, such as OA and RA.Joint inflammation begins with cartilage breakdown in OA, whereas the process affects mainly the synovial membrane in RA (Gardner, 1994). Despite this difference, prostaglandins, primarily those derived from COX-2, are key mediators for inflammation and pain in both types of arthritis. Consequently, inhibition of COX-2 and prostaglandin synthesis by Article, publication date, and citation information can be found at

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Section: Discussionmentioning

confidence: 99%

MF498 [N-{[4-(5,9-Diethoxy-6-oxo-6,8-dihydro-7H-pyrrolo[3,4-g]quinolin-7-yl)-3-methylbenzyl]sulfonyl}-2-(2-methoxyphenyl)acetamide], a Selective E Prostanoid Receptor 4 Antagonist, Relieves Joint Inflammation and Pain in Rodent Models of Rheumatoid and Osteoarthritis

Clark¹,

Rowland²,

Denis³

et al. 2008

J Pharmacol Exp Ther

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“…The series reported by Merck (Ruel et al, 1999) contains a tricyclic system similar to the Searle series. A (Ducharme et al, 2005;Clark et al, 2008) and GW-848687 (Giblin et al, 2007), shown in Fig. 5.…”

Section: Distribution and Biological Functionsmentioning

confidence: 99%

International Union of Basic and Clinical Pharmacology. LXXXIII: Classification of Prostanoid Receptors, Updating 15 Years of Progress

Woodward

Jones

Narumiya³

2011

Pharmacol Rev

396

414

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“…PTGER1 receptor antagonists have been shown to have an excellent profile in inflammatory models [16]. So far, the activation of PTGER1 has been shown to specifically activate the action of aldosterone on epithelial sodium channels expression in the renal medulla [17].…”

Section: Discussionmentioning

confidence: 99%

Identification of prostaglandin receptors in human ureters

et al. 2012

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BackgroundProstaglandins play an important role in ureteral obstruction, but the detailed expression profiles of the prostaglandin receptors (PTGER1, PTGER2, PTGER3, PTGER4, PTGFR) remain unknown in the different parts of the human ureter.MethodsThe expression pattern of PTGER1, PTGER2, PTGER3, PTGER4 and PTGFR was determined in human distal, mid and proximal ureter and renal pelvis samples using immunohistochemistry (protein levels) and quantitative real-time PCR (mRNA).ResultsPTGER1 was highly expressed in most samples irrespective of the ureteral localization; however, urothelial cells had higher levels of PTGER1 than smooth muscle cells. PTGFR was also moderately to strongly expressed in urothelial and smooth muscle cells. In comparison, PTGER2-4 expression was mostly unexpressed or weakly expressed in urothelial and smooth cells in all regions.ConclusionsOur data indicate high levels of PTGER1 in ureters.

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The discovery of 6-[2-(5-chloro-2-{[(2,4-difluorophenyl)methyl]oxy}phenyl)-1-cyclopenten-1-yl]-2-pyridinecarboxylic acid, GW848687X, a potent and selective prostaglandin EP1 receptor antagonist for the treatment of inflammatory pain

Cited by 42 publications

References 33 publications

MF498 [N-{[4-(5,9-Diethoxy-6-oxo-6,8-dihydro-7H-pyrrolo[3,4-g]quinolin-7-yl)-3-methylbenzyl]sulfonyl}-2-(2-methoxyphenyl)acetamide], a Selective E Prostanoid Receptor 4 Antagonist, Relieves Joint Inflammation and Pain in Rodent Models of Rheumatoid and Osteoarthritis

MF498 [N-{[4-(5,9-Diethoxy-6-oxo-6,8-dihydro-7H-pyrrolo[3,4-g]quinolin-7-yl)-3-methylbenzyl]sulfonyl}-2-(2-methoxyphenyl)acetamide], a Selective E Prostanoid Receptor 4 Antagonist, Relieves Joint Inflammation and Pain in Rodent Models of Rheumatoid and Osteoarthritis

International Union of Basic and Clinical Pharmacology. LXXXIII: Classification of Prostanoid Receptors, Updating 15 Years of Progress

Identification of prostaglandin receptors in human ureters

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