MF498 is a novel and selective EP4 antagonist [1].
Prostaglandin E2 receptors (EP) are G-protein coupled receptors (GPCRs) and functions with the binding of Prostaglandin (PG) E2. The EPs exhibit differences in signal transduction, tissue localization, and regulation of expression. The EP4 receptor is over-expressed in human prostate cancer tissue [2].
In vitro: MF498 was a selective EP4 receptor antagonist with the Ki of 0.7 nM while the Ki > 1 μM for other EP receptors. In HEK293 cells expressing human EP4 receptor, MF498 inhibited EP ligand-induced activity with an IC50 value of 1.7 nM [1].
In vivo: In rodent models of rheumatoid and osteoarthritis, MF498 inhibited inflammation without gastrointestinal toxicity, the ED50 values was as low as 0.02 mg/kg/day[1].In adjuvant-induced arthritis (AIA) rat model for rheumatoid arthritis (RA), MF498 inhibited inflammation. In addition, MF498 was effective in relieving OA-like pain in guinea pigs. In rat models of gastrointestinal toxicity, MF498 was well tolerated, causing no mucosal leakage or erosions. In a furosemide-induced diuresis model, MF498 reduced furosemide-induced natriuresis by 50% [3].
References:
[1] P. Clark, S. E. Rowland, D. Denis, et al. 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.Journal of Pharmacology and Experimental Therapeutics 325(2), 425-434 (2008).
[2] Sugimoto Y, Narumiya S. Prostaglandin E receptors[J]. Journal of Biological Chemistry, 2007, 282(16): 11613-11617.
[3] Clark P, Rowland S E, Denis D, et al. 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[J]. Journal of Pharmacology and Experimental Therapeutics, 2008, 325(2): 425-434.