title: Fragment-based discovery of novel and selective mPGES-1 inhibitors Part 1: identification of sulfonamido-1,2,3-triazole-4,5-dicarboxylic acid.
abstract: Microsomal prostaglandin E synthase-1 (mPGES-1) is an inducible prostaglandin E synthase that catalyzes the conversion of prostaglandin PGH(2) to PGE(2) and represents a novel target for therapeutic treatment of inflammatory disorders. It is essential to identify mPGES-1 inhibitor with novel scaffold as new hit or lead compound for the purpose of the next-generation anti-inflammatory drugs. Herein we report the discovery of sulfonamido-1,2,3-triazole-4,5-dicarboxylic derivatives as a novel class of mPGES-1 inhibitors identified through fragment-based virtual screening and in vitro assays on the inhibitory activity of the actual compounds. 1-[2-(N-Phenylbenzenesulfonamido)ethyl]-1H-1,2,3-triazole-4,5-dicarboxylic acid (6f) inhibits human mPGES-1 (IC(50) of 1.1 μM) with high selectivity (ca.1000-fold) over both COX-1 and COX-2 in a cell-free assay. In addition, the activity of compound 6f was again tested at 10 μM concentration in presence of 0.1% Triton X-100 and found to be reduced to 1/4 of its original activity without this detergent. Compared to the complete loss of activity of nuisance inhibitor with the detergent, therefore, compound 6f would be regarded as a partial nuisance inhibitor of mPGES-1 with a novel scaffold for the optimal design of more potent mPGES-1 inhibitors.
authors.affiliation: Research Institute for Basic Sciences and Department of Chemistry, College of Sciences, Kyung Hee University, Seoul 130-701, Republic of Korea.
authors.forename: Kijae
authors.initials: K
authors.lastname: Lee
authors.forename: Van Chung
authors.initials: VC
authors.lastname: Pham
authors.forename: Min Ji
authors.initials: MJ
authors.lastname: Choi
authors.forename: Kyung Ju
authors.initials: KJ
authors.lastname: Kim
authors.forename: Kyung-Tae
authors.initials: KT
authors.lastname: Lee
authors.forename: Seong-Gu
authors.initials: SG
authors.lastname: Han
authors.forename: Yeon Gyu
authors.initials: YG
authors.lastname: Yu
authors.forename: Jae Yeol
authors.initials: JY
authors.lastname: Lee
mesh_terms: D001665:Binding Sites; D020134:Catalytic Domain; D018360:Crystallography, X-Ray; D003998:Dicarboxylic Acids / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D019746:Intramolecular Oxidoreductases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008861:Microsomes / Q000201:enzymology; D062105:Molecular Docking Simulation; D000071876:Prostaglandin-E Synthases; D011485:Protein Binding; D013449:Sulfonamides / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D013816:Thermodynamics; D014230:Triazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism
chemical_list: C581248:1-(2-(N-phenylbenzenesulfonamido)ethyl)-1H-1,2,3-triazole-4,5-dicarboxylic acid; D003998:Dicarboxylic Acids; D004791:Enzyme Inhibitors; D013449:Sulfonamides; D014230:Triazoles; D019746:Intramolecular Oxidoreductases; C000605862:PTGES protein, human; D000071876:Prostaglandin-E Synthases