Microsomal prostaglandin E synthase-1 (mPGES-1) converts the COX product PGH2 into the biologically active PGE2.[1] Like COX-2, the expression of mPGES-1 is induced in response to pro-inflammatory mediators, including LPS, IL-1β, and TNF-α.[2] AF3485 is a selective 3-aminocarbazole inhibitor of mPGES-1, blocking the synthesis of PGE2 but not PGF2α in A549 cells stimulated with IL-1β (IC50s = 2.9 and >100 µM, respectively).[3] It reduces inflammatory pain (acetic acid-induced writhing) in mice by 74% when given intraperitoneally at 10 mg/kg.[3] AF3485 is absorbed through enterocytes, is metabolically stable in human and rat microsome preparations, and is bioavailable in vivo.[3]
References
1. 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. Proc. Natl. Acad. Sci. USA 96(13), 7220-7225 (1999).
2. Stichtenoth, D.O., Thorén, S., Bian, H., et al. Microsomal prostaglandin E synthase is regulated by proinflammatory cytokines and glucocorticoids in primary rheumatoid synovial cells. J. Immunol. 167, 469-474 (2001).
3. Alisi, M.A., Cazzolla, N., Coletta, I., et al. 3-Aminocarbazole compound, pharmaceutical composition containing it and preparation method therefor. PCT/EP2009/055652, 1-38 (2009).