title: Inhibition of microsomal prostaglandin E synthase-1 by aminothiazoles decreases prostaglandin E2 synthesis in vitro and ameliorates experimental periodontitis in vivo.
abstract: The potent inflammatory mediator prostaglandin E2 (PGE2) is implicated in the pathogenesis of several chronic inflammatory conditions, including periodontitis. The inducible enzyme microsomal prostaglandin E synthase-1 (mPGES-1), catalyzing the terminal step of PGE2 biosynthesis, is an attractive target for selective PGE2 inhibition. To identify mPGES-1 inhibitors, we investigated the effect of aminothiazoles on inflammation-induced PGE2 synthesis in vitro, using human gingival fibroblasts stimulated with the cytokine IL-1β and a cell-free mPGES-1 activity assay, as well as on inflammation-induced bone resorption in vivo, using ligature-induced experimental periodontitis in Sprague-Dawley rats. Aminothiazoles 4-([4-(2-naphthyl)-1,3-thiazol-2-yl]amino)phenol (TH-848) and 4-(3-fluoro-4-methoxyphenyl)-N-(4-phenoxyphenyl)-1,3-thiazol-2-amine (TH-644) reduced IL-1β-induced PGE2 production in fibroblasts (IC50 1.1 and 1.5 μM, respectively) as well as recombinant mPGES-1 activity, without affecting activity or expression of the upstream enzyme cyclooxygenase-2. In ligature-induced experimental periodontitis, alveolar bone loss, assessed by X-ray imaging, was reduced by 46% by local treatment with TH-848, compared to vehicle, without any systemic effects on PGE2, 6-keto PGF1α, LTB4 or cytokine levels. In summary, these results demonstrate that the aminothiazoles represent novel mPGES-1 inhibitors for inhibition of PGE2 production and reduction of bone resorption in experimental periodontitis, and may be used as potential anti-inflammatory drugs for treatment of chronic inflammatory diseases, including periodontitis.
authors: Division of Periodontology, Department of Dental Medicine, Karolinska Institutet, Huddinge, Sweden.
authors: Anna
authors: A
authors: Kats
authors: Tove
authors: T
authors: Båge
authors: Pierre
authors: P
authors: Georgsson
authors: Jörgen
authors: J
authors: Jönsson
authors: Hernán Concha
authors: HC
authors: Quezada
authors: Anders
authors: A
authors: Gustafsson
authors: Leif
authors: L
authors: Jansson
authors: Claes
authors: C
authors: Lindberg
authors: Karin
authors: K
authors: Näsström
authors: Tülay
authors: T
authors: Yucel-Lindberg
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D051546:Cyclooxygenase 2 / Q000378:metabolism; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology; D015232:Dinoprostone / Q000037:antagonists & inhibitors* / Q000096:biosynthesis*; D006801:Humans; D019746:Intramolecular Oxidoreductases / Q000037:antagonists & inhibitors* / Q000096:biosynthesis*; D008861:Microsomes / Q000187:drug effects / Q000201:enzymology; D010518:Periodontitis / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism; D011448:Prostaglandin Antagonists / Q000494:pharmacology*; D000071876:Prostaglandin-E Synthases; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013844:Thiazoles / Q000494:pharmacology*
chemical_list: C582623:4-((4-(2-naphthyl)-1,3-thiazol- 2-yl)amino)phenol; C582622:4-(3-fluoro-4- methoxyphenyl)-N-(4-phenoxyphenyl)-1,3-thiazol-2-amine; D052246:Cyclooxygenase 2 Inhibitors; D011448:Prostaglandin Antagonists; D013844:Thiazoles; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; C489691:Ptgs2 protein, rat; D019746:Intramolecular Oxidoreductases; C000605862:PTGES protein, human; D000071876:Prostaglandin-E Synthases; C497818:Ptges protein, rat; D015232:Dinoprostone
keywords: PGE2; anti-inflammatory; cyclooxygenase-2; gingival fibroblasts; interleukin-1β; mPGES-1 inhibitor