title: Discovery of benzo[g]indol-3-carboxylates as potent inhibitors of microsomal prostaglandin E(2) synthase-1.
abstract: Selective inhibition of pro-inflammatory prostaglandin (PG)E(2) formation via microsomal PGE(2) synthase-1 (mPGES-1) might be superior over inhibition of all cyclooxygenase (COX)-derived products by non-steroidal anti-inflammatory drugs (NSAIDs) and coxibs. We recently showed that benzo[g]indol-3-carboxylates potently suppress leukotriene biosynthesis by inhibiting 5-lipoxygenase. Here, we describe the discovery of benzo[g]indol-3-carboxylates as a novel class of potent mPGES-1 inhibitors (IC(50)0.1 microM). Ethyl 2-(3-chlorobenzyl)-5-hydroxy-1H-benzo[g]indole-3-carboxylate (compound 7a) inhibits human mPGES-1 in a cell-free assay (IC(50)=0.6 microM) as well as in intact A549 cells (IC(50)=2 microM), and suppressed PGE(2) pleural levels in rat carrageenan-induced pleurisy. Inhibition of cellular COX-1/2 activity was significantly less pronounced. Compound 7a significantly reduced inflammatory reactions in the carrageenan-induced mouse paw edema and rat pleurisy. Together, based on the select and potent inhibition of mPGES-1 and 5-lipoxygenase, benzo[g]indol-3-carboxylates possess potential as novel anti-inflammatory drugs with a valuable pharmacological profile.
authors.affiliation: Department of Pharmaceutical Analytics, Pharmaceutical Institute, Eberhard Karls University Tuebingen, Auf der Morgenstelle 8, D-72076 Tuebingen, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Koeberle
authors.forename: Eva-Maria
authors.initials: EM
authors.lastname: Haberl
authors.forename: Antonietta
authors.initials: A
authors.lastname: Rossi
authors.forename: Carlo
authors.initials: C
authors.lastname: Pergola
authors.forename: Friederike
authors.initials: F
authors.lastname: Dehm
authors.forename: Hinnak
authors.initials: H
authors.lastname: Northoff
authors.forename: Reinhard
authors.initials: R
authors.lastname: Troschuetz
authors.forename: Lidia
authors.initials: L
authors.lastname: Sautebin
authors.forename: Oliver
authors.initials: O
authors.lastname: Werz
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D002264:Carboxylic Acids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004487:Edema / Q000188:drug therapy / Q000201:enzymology; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D019746:Intramolecular Oxidoreductases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D051379:Mice; D008861:Microsomes; D010998:Pleurisy / Q000188:drug therapy / Q000201:enzymology; D000071876:Prostaglandin-E Synthases; D051381:Rats; D017208:Rats, Wistar; D021241:Spectrometry, Mass, Electrospray Ionization
chemical_list: D000893:Anti-Inflammatory Agents; D002264:Carboxylic Acids; D004791:Enzyme Inhibitors; D007211:Indoles; D019746:Intramolecular Oxidoreductases; C000605862:PTGES protein, human; D000071876:Prostaglandin-E Synthases; C000605865:Ptges protein, mouse