MF63, a lead compound from a series of phenanthrene imidazole inhibitors made by Merck Frost, Quebec, Canada, with antipyretic and analgesic properties, is a candidate anti-inflammatory drug. MF63 is a selective inhibitor of mPGES-1 with high degree of selectivity over mPGES-2, PGI2, PGD2, and thromboxane (TX) synthases, Cox-1, Cox-2, 5-lipoxygenase, and various prostanoid and leukotriene receptors. It is a potent inhibitor of human (IC50 of 1.3 nM) and guinea pig (IC50 of 0.9 nM) mPGES-1, but displays little activity toward the rat or mouse enzyme. In a knock-in (KI) mouse, expressing human mPGES-1 and in guinea pig the compound selectively suppressed the synthesis of PGE(2), 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. MF63 demonstrated effective relief of both pyresis and inflammatory pain in mice or nonhuman primates’ preclinical models of inflammation. In the guinea pig, MF63 strongly inhibited LPS-induced pyresis and hyperalgesia and relieved chronic osteoarthritic pain at 30–100 mg/kg. MF63 did not cause NSAID-like gastrointestinal toxic effects, such as mucosal erosions or leakage in mice.