title: Structural optimization and biological evaluation of 2-substituted 5-hydroxyindole-3-carboxylates as potent inhibitors of human 5-lipoxygenase.
abstract: Pharmacological suppression of leukotriene biosynthesis by inhibitors of 5-lipoxygenase (5-LO) is a strategy to intervene with inflammatory and allergic disorders. We recently presented 2-amino-5-hydroxy-1H-indoles as efficient 5-LO inhibitors in cell-based and cell-free assays. Structural optimization led to novel benzo[g]indole-3-carboxylates exemplified by ethyl 2-(3-chlorobenzyl)-5-hydroxy-1H-benzo[g]indole-3-carboxylate (compound 11a), which inhibits 5-LO activity in human neutrophils and recombinant human 5-LO with IC(50) values of 0.23 and 0.086 microM, respectively. Notably, 11a efficiently blocks 5-LO product formation in human whole blood assays (IC(50) = 0.83-1.6 microM) and significantly prevented leukotriene B(4) production in pleural exudates of carrageenan-treated rats, associated with reduced severity of pleurisy. Together, on the basis of their high potency against 5-LO and the marked efficacy in biological systems, these novel and straightforward benzo[g]indole-3-carboxylates may have potential as anti-inflammatory therapeutics.
authors.affiliation: Department of Chemistry and Pharmacy, Chair of Pharmaceutical Chemistry, Friedrich Alexander University Erlangen, Erlangen, Germany.
authors.forename: Eva-Maria
authors.initials: EM
authors.lastname: Karg
authors.forename: Susann
authors.initials: S
authors.lastname: Luderer
authors.forename: Carlo
authors.initials: C
authors.lastname: Pergola
authors.forename: Ulrike
authors.initials: U
authors.lastname: Bühring
authors.forename: Antonietta
authors.initials: A
authors.lastname: Rossi
authors.forename: Hinnak
authors.initials: H
authors.lastname: Northoff
authors.forename: Lidia
authors.initials: L
authors.lastname: Sautebin
authors.forename: Reinhard
authors.initials: R
authors.lastname: Troschütz
authors.forename: Oliver
authors.initials: O
authors.lastname: Werz
mesh_terms: D000818:Animals; D002351:Carrageenan; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D016859:Lipoxygenase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D009504:Neutrophils / Q000187:drug effects; D010998:Pleurisy / Q000139:chemically induced / Q000188:drug therapy; D051381:Rats; D013329:Structure-Activity Relationship
chemical_list: D007211:Indoles; D016859:Lipoxygenase Inhibitors; C026785:5-hydroxyindole; D002351:Carrageenan