title: 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.
abstract: 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, MF266-1 [1-(5-{3-[2-(benzyloxy)-5-chlorophenyl]-2-thienyl}pyridin-3-yl)-2,2,2-trifluoroethane-1,1-diol] or EP3 MF266-3 [(2E)-N-[(5-bromo-2-methoxyphenyl)sulfonyl]-3-[5-chloro-2-(2-naphthylmethyl)phenyl]acrylamide], 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 furosemide-induced natriuresis by approximately 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.
authors.affiliation: Department of Pharmacology, Merck Frosst Centre for Therapeutic Research, 16711 Trans Canada Hwy, Kirkland, QC H9H 3L1, Canada.
authors.forename: Patsy
authors.initials: P
authors.lastname: Clark
authors.forename: Steven E
authors.initials: SE
authors.lastname: Rowland
authors.forename: Danielle
authors.initials: D
authors.lastname: Denis
authors.forename: Marie-Claude
authors.initials: MC
authors.lastname: Mathieu
authors.forename: Rino
authors.initials: R
authors.lastname: Stocco
authors.forename: Hugo
authors.initials: H
authors.lastname: Poirier
authors.forename: Jason
authors.initials: J
authors.lastname: Burch
authors.forename: Yongxin
authors.initials: Y
authors.lastname: Han
authors.forename: Laurent
authors.initials: L
authors.lastname: Audoly
authors.forename: Alex G
authors.initials: AG
authors.lastname: Therien
authors.forename: Daigen
authors.initials: D
authors.lastname: Xu
mesh_terms: D000700:Analgesics / Q000627:therapeutic use*; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000627:therapeutic use*; D001169:Arthritis, Experimental / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism; D001172:Arthritis, Rheumatoid / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism; D002460:Cell Line; D045744:Cell Line, Tumor; D000242:Cyclic AMP / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000235:genetics; D005665:Furosemide / Q000494:pharmacology; D006168:Guinea Pigs; D006801:Humans; D007249:Inflammation / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D008297:Male; D009318:Natriuresis / Q000187:drug effects; D010003:Osteoarthritis / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism; D010146:Pain / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism; D011804:Quinolines / Q000627:therapeutic use*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D018078:Receptors, Prostaglandin E / Q000819:agonists / Q000037:antagonists & inhibitors*; D058309:Receptors, Prostaglandin E, EP4 Subtype; D013449:Sulfonamides / Q000627:therapeutic use*
chemical_list: D000700:Analgesics; D000893:Anti-Inflammatory Agents; C528911: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; C545650:PTGER4 protein, human; C545651:Ptger4 protein, mouse; C545652:Ptger4 protein, rat; D011804:Quinolines; D012333:RNA, Messenger; D018078:Receptors, Prostaglandin E; D058309:Receptors, Prostaglandin E, EP4 Subtype; D013449:Sulfonamides; D005665:Furosemide; D000242:Cyclic AMP; D051546:Cyclooxygenase 2