期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 54, 期 6, 页码 1565-1575出版社
AMER CHEMICAL SOC
DOI: 10.1021/jm101238d
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资金
- University of Salerno
- Minister dell'Istruzione, dell'Universita e della Ricerca (MIUR)
- Aureliasan GmbH (Tuebingen, Germany)
Microsomal prostaglandin E-2 synthase (mPGES)-1 catalyzes the transformation of PGH(2) to PGE(2) that is involved in several pathologies like fever, pain, and inflammatory disorders. To identify novel mPGES-1 inhibitors, we used in silico screening to rapidly direct the synthesis, based on the copper-catalyzed 3 + 2 Huisgen's reaction (click chemistry), of potential inhibitors. We designed 26 new triazole-based compounds in accordance with the pocket binding requirements of human mPGES-1. Docking results, in agreement with ligand efficiency values, suggested the synthesis of 15 compounds that at least in theory were shown to be more efficient in inhibiting mPGES-1. Biological evaluation of these selected compounds has disclosed three new potential anti-inflammatory drugs: (I) compound 4 displaying selectivity for mPGES-1 with an IC50 value of 3.2 mu M, (II) compound 20 that dually inhibits 5-lipoxygenase and mPGES-1, and (III) compound 7 apparently acting as 5-lipoxygenase-activating protein inhibitor (IC50 = 0.4 mu M).
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