PF-9184 is a novel mPGES-1 inhibitor [1]. Microsomal prostaglandin E synthase-1 (mPGES-1) is an inducible terminal isomerase expressed in cytokine-sensitive brain endothelial cells. mPGES-1 functions as the central switch during immune-induced pyresis and as a target for treatment of fever and other PGE2-dependent acute phase reactions elicited by the brain [2]. mPGES-1 has been incolved in the formation of PGE2 essential for pain hypersensitivity and inflammation. Microsomal prostaglandin E synthase-1 (mPGES-1) has been involved in converting the COX product prostaglandin H2 (PGH2) into the biologically active PGE2[3].
In vitro: PF-9184 potently inhibited recombinant human mPGES-1 with an IC50 value of 16.5 ± 3.8 nM. PF-9184 showed no effect on rhCOX-1 and rhCOX-2 with >6500-fold selectivity. In rationally designed cell systems, PF-9184 inhibited PGE2 synthesis with IC50 in the range of 0.5–5 μM in serum-free cell and human whole blood cultures, while sparing the synthesis of 6-keto-PGF1α (PGF1α) and PGF2α[1]. PF-9184 showed no apparent cytotoxic effects up to 100 μM [1].
References:
[1] Mbalaviele G, Pauley A M, Shaffer A F, et al. Distinction of microsomal prostaglandin E synthase-1 (mPGES-1) inhibition from cyclooxygenase-2 inhibition in cells using a novel, selective mPGES-1 inhibitor[J]. Biochemical pharmacology, 2010, 79(10): 1445-1454.
[2] Engblom D, Saha S, Engstrm L, et al. Microsomal prostaglandin E synthase-1 is the central switch during immune-induced pyresis[J]. Nature neuroscience, 2003, 6(11): 1137-1138.
[3] Jakobsson P J, Thorén S, Morgenstern R, et al. Identification of human prostaglandin E synthase: a microsomal, glutathione-dependent, inducible enzyme, constituting a potential novel drug target[J]. Proceedings of the National Academy of Sciences, 1999, 96(13): 7220-7225.