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INFLAMMATION, IMMUNOPHARMACOLOGY, AND ASTHMA

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

Departments of Pharmacology (D.X., S.E.R., P.C., M.S., L.A., D.R.), Biochemistry and Molecular Biology (S.G., N.M., J.M.), and Medicinal Chemistry (A.G., B.C., Y.D., R.W.F.), Merck Frosst Centre for Therapeutic Research, Kirkland, Quebec, Canada

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.

Address correspondence to: Daigen Xu, Department of Pharmacology, Merck Frosst Centre for Therapeutic Research, 16711 Trans Canada Hwy, Kirkland, QC, Canada H9H 3L1. E-mail: daigen_xu{at}merck.com