Description
Microsomal prostaglandin E synthase-1 (mPGES-1) converts the COX product prostaglandin H2 (PGH2; ) into the biologically active PGE2 . Like COX-2, the expression of mPGES-1 is induced in response to pro-inflammatory mediators, including LPS, IL-1β, and TNF-α. PF-9184 is a potent inhibitor of mPGES-1 (IC50 = 16.5 nM for recombinant human enzyme). It displays at least 6,500-fold selectivity for mPGES-1 over COX-1 and COX-2. PF-9184 blocks the synthesis of PGE2 in LPS-treated human whole blood and in IL-1β-stimulated fibroblasts (IC50s = 0.4-5 μM).
Uses
PF 9184 is a?microsomal prostaglandin E?synthase-1(mPGES-1) inhibitor. mPGES-1is an enzyme induced during the inflammatory response and it is an attractive target for developing anti-inflammatory drugs.
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].
Enzyme inhibitor
This potent mPGES-1 inhibitor (FW = 461.32 g/mol; CAS 1221971-47-6; Solubility: 100 mM in DMSO), also named N-[3',4'-dichloro(1,1'- biphenyl)yl]-4-hydroxy-2H-1,2-benzothiazine-3-carboxamide 1,1-dioxide), targets human and rat microsomal prostaglandin E synthase 1, with respective IC50 values of 16.5 nM and 1.08 μM, exhibiting >6500x selectivity toward mPGES-1 versus COX1 and COX2. PF-9184 inhibits IL- 1β-induced PGE2 synthesis in vitro. In inflammation and clinically relevant biological systems, mPGES-1 expression, like COX-2 expression is induced in cell context- and time-dependent manner, a behavior that is fully consistent with the kinetics of PGE2 synthesis
in vivo
PF-9184 (oral administration or even local delivery) has no effect on PGE2 synthesis in recombinant rats[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.
