title: Synthesis and pharmacological characterization of benzenesulfonamides as dual species inhibitors of human and murine mPGES-1.
abstract: The microsomal prostaglandin E2 synthase 1 (mPGES-1) became a desirable target in recent years for the research of new anti-inflammatory drugs. Even though many potent inhibitors of human mPGES-1, tested in vitro assay systems, have been synthesized, they all failed in preclinical trials in rodent models of inflammation, due to the lack of activity on rodent enzyme. Within this work we want to present a new class of mPGES-1 inhibitors derived from a benzenesulfonamide scaffold with inhibitory potency on human and murine mPGES-1. Starting point with an IC50 of 13.8 μM on human mPGES-1 was compound 1 (4-{benzyl[(4-methoxyphenyl)methyl]sulfamoyl}benzoic acid; FR4), which was discovered by a virtual screening approach. Optimization during a structure-activity relationship (SAR) process leads to compound 28 (4-[(cyclohexylmethyl)[(4-phenylphenyl)methyl]sulfamoyl]benzoic acid) with an improved IC50 of 0.8 μM on human mPGES-1. For the most promising compounds a broad pharmacological characterization has been carried out to estimate their anti-inflammatory potential.
authors.affiliation: Institute of Pharmaceutical Chemistry, Goethe-University Frankfurt, Max-von-Laue-Str. 9, D-60438 Frankfurt am Main, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Hanke
authors.forename: Florian
authors.initials: F
authors.lastname: Rörsch
authors.forename: Theresa M
authors.initials: TM
authors.lastname: Thieme
authors.forename: Nerea
authors.initials: N
authors.lastname: Ferreiros
authors.forename: Gisbert
authors.initials: G
authors.lastname: Schneider
authors.forename: Gerd
authors.initials: G
authors.lastname: Geisslinger
authors.forename: Ewgenij
authors.initials: E
authors.lastname: Proschak
authors.forename: Sabine
authors.initials: S
authors.lastname: Grösch
authors.forename: Manfred
authors.initials: M
authors.lastname: Schubert-Zsilavecz
mesh_terms: D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006367:HeLa Cells; D006801:Humans; D019746:Intramolecular Oxidoreductases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008024:Ligands; D051379:Mice; D015394:Molecular Structure; D041681:NIH 3T3 Cells; D000071876:Prostaglandin-E Synthases; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000096926:Benzenesulfonamides
chemical_list: D004791:Enzyme Inhibitors; D019746:Intramolecular Oxidoreductases; D008024:Ligands; D000071876:Prostaglandin-E Synthases; D013449:Sulfonamides; D000096926:Benzenesulfonamides; C000605862:PTGES protein, human; C000605865:Ptges protein, mouse
keywords: Human mPGES-1; Inflammation; Inhibitors; Murine mPGES-1; SAR; Sulfonamides