IC50: 0.9 and 1.3 nM for pig mPGES-1 and human mPGES-1

MF63 is a potent, selective and orally active mPGES-1 inhibitor. Microsomal prostaglandin E synthase-1 (mPGES-1) is a terminal prostaglandin E2 synthase in the cyclooxygenase pathway. Thus, inhibitors of mPGES-1 may block prostaglandin E2 production and relieve inflammatory symptoms.

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].

Clinical trial: N/A

Reference:
[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.