Description
Microsomal prostaglandin E2 synthase-1 (mPGES-1) is the terminal enzyme in the biosynthesis of PGE2. MF63 is a potent, selective, and orally active inhibitor of human mPGES-1 (IC50 = 1.3 nM). It displays greater than 1,000-fold selectivity over other prostanoid synthases. MF63 also potently inhibits guinea pig mPGES-1 (IC50 = 0.9 nM) but not mouse or rat mPGES-1. In guinea pigs or in mice expressing human mPGES-1, MF63 prevents LPS-induced pyresis, hyperalgesia, and iodoacetate-induced osteoarthritic pain. It does not produce the gastrointestinal toxicity that is caused by non-selective COX inhibitors, although it markedly suppresses PGE2 synthesis in the stomach.
Uses
MF 63 is a microsomal prostaglandin E2 synthase-1 (mPGES-1) the final enzyme in the synthesis of PGE2. Prevents LPS-induced hyperglasia. Anti-inflammatory, analgesic, anti-cancer agent.
in vitro
mf63 was found to be significantly more potent than those previously reported mpges-1 inhibitors with an intrinsic inhibitory potency on the recombinant human mpges-1 enzyme. furthermore, mf63 showed a pge2 whole cell inhibition in a549 cells and a human whole blood activity [1].
in vivo
in rodent species, mf63 inhibited guinea pig mpges-1 strongly but not the mouse or rat enzyme. when tested in the guinea pig and a knock-in (ki) mouse expressing human mpges-1, mf63 suppressed the synthesis of pge2 selectively, but not other prostaglandins that were inhibitable by nonsteroidal anti-inflammatory drugs (nsaid), yet remaided nsaid-like efficacy at inhibiting lipopolysaccharide-induced hyperalgesia, pyresis, and iodoacetate-induced osteoarthritic pain. additionally, mf63 did not cause nsaid-like gastrointestinal toxic effects, such as mucosal erosions or leakage in the ki mice or nonhuman primates, although mf63 markedly inhibited pge2 synthesis in the ki mouse stomach [1].
IC 50
0.9 and 1.3 nm for pig mpges-1 and human mpges-1
References
[1] xu d,rowland se,clark p,giroux a,cté b,guiral s,salem m,ducharme y,friesen rw,méthot n,mancini j,audoly l,riendeau d. 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.2008 sep;326(3):754-63.
