Abstract
Microsomal prostaglandin E synthase-1 (mPGES-1) is a terminal prostaglandin E2 (PGE2) synthase in the cyclooxygenase pathway. Inhibitors of mPGES-1 may block PGE2 production and relieve inflammatory symptoms. To test the hypothesis, we evaluated the antipyretic and analgesic properties of a novel and selective mPGES-1 inhibitor, MF63 [2-(6-chloro-1H-phenanthro-[9,10-d]imidazol-2-yl)isophthalonitrile], in animal models of inflammation. MF63 potently inhibited the human mPGES-1 enzyme (IC50 = 1.3 nM), with a high degree (>1000-fold) of selectivity over other prostanoid synthases. In rodent species, MF63 strongly inhibited guinea pig mPGES-1 (IC50 = 0.9 nM) but not the mouse or rat enzyme. When tested in the guinea pig and a knock-in (KI) mouse expressing human mPGES-1, the compound selectively suppressed the synthesis of PGE2, but not other prostaglandins inhibitable by nonsteroidal anti-inflammatory drugs (NSAIDs), yet retained NSAID-like efficacy at inhibiting lipopolysaccharide-induced pyresis, hyperalgesia, and iodoacetate-induced osteoarthritic pain. In addition, MF63 did not cause NSAID-like gastrointestinal toxic effects, such as mucosal erosions or leakage in the KI mice or nonhuman primates, although it markedly inhibited PGE2 synthesis in the KI mouse stomach. Our data demonstrate that mPGES-1 inhibition leads to effective relief of both pyresis and inflammatory pain in preclinical models of inflammation and may be a useful approach for treating inflammatory diseases.
Footnotes
-
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
-
doi:10.1124/jpet.108.138776.
-
ABBREVIATIONS: NSAID, nonsteroidal anti-inflammatory drug; COX, cyclooxygenase; EIA, enzyme immunoassay; EP, E prostanoid receptor; FBS, fetal bovine serum; kb, kilo base; KI, knock-in; LPS, lipopolysaccharide; L/R ratio, weight bearing ratio between left/right forelimbs; MF63, 2-(6-chloro-1H-phenanthro[9,10-d]imidazol-2-yl)isophthalonitrile; MF-tricyclic, 3-(3,4-difluorophenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone; MIA, monosodium iodoacetate; mPGES, microsomal prostaglandin E synthase; PG, prostaglandin; 6-keto-PGF1α, 6-keto-prostaglandin F1α; TXB2, thromboxane B2; WT, wild type; IL, interleukin; PBS, phosphate-buffered saline; DMSO, dimethyl sulfoxide; PCR, polymerase chain reaction; PWL, paw withdrawal latency.
- Received March 11, 2008.
- Accepted May 12, 2008.
- The American Society for Pharmacology and Experimental Therapeutics
JPET articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|