title: Structure-activity relationship of nonacidic quinazolinone inhibitors of human microsomal prostaglandin synthase 1 (mPGES 1).
abstract: Microsomal prostaglandin E synthase 1 (mPGES-1) is a key enzyme of the arachidonic acid cascade. Its product PGE(2) plays an important role in various inflammatory processes, pain, fever, and cancer. Selective inhibition of mPGES-1 might be a promising step to avoid cyclooxygenase-related effects of NSAIDs. We studied a class of quinazolinone derivatives of the lead structure FR20 for their effects on the isolated human and murine enzymes, human HeLa cells, and in various settings of the whole blood assay. Novel compounds with direct enzyme inhibiting activity in the submicromolar range (IC(50): 0.13-0.37 μM) were designed using a bioisosteric replacement strategy and proved to be effective in both cells and human whole blood. Furthermore, pharmacological profiling of toxicity and eicosanoid screening with LC/MS-MS was applied to characterize this new class of mPGES-1 inhibitors.
authors.affiliation: Johann Wolfgang Goethe-University, Institute of Clinical Pharmacology, pharmazentrum frankfurt, LiFF/ZAFES, Theodor-Stern-Kai 7, D-60590 Frankfurt/Main, Germany. Roersch@em.uni-frankfurt.de
authors.forename: Florian
authors.initials: F
authors.lastname: Rörsch
authors.forename: Estella
authors.initials: E
authors.lastname: Buscató
authors.forename: Klaus
authors.initials: K
authors.lastname: Deckmann
authors.forename: Gisbert
authors.initials: G
authors.lastname: Schneider
authors.forename: Manfred
authors.initials: M
authors.lastname: Schubert-Zsilavecz
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
mesh_terms: D000818:Animals; D001682:Biological Availability; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000097:blood / Q000138:chemical synthesis / Q000494:pharmacology*; D006367:HeLa Cells; D006801:Humans; D019746:Intramolecular Oxidoreductases / Q000037:antagonists & inhibitors*; D051379:Mice; D008861:Microsomes / Q000187:drug effects / Q000201:enzymology; D000071876:Prostaglandin-E Synthases; D052999:Quinazolinones / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D052999:Quinazolinones; D019746:Intramolecular Oxidoreductases; C000605862:PTGES protein, human; D000071876:Prostaglandin-E Synthases; C000605865:Ptges protein, mouse