title: Identification of 6-benzyloxysalicylates as a novel class of inhibitors of 15-lipoxygenase-1.
abstract: Lipoxygenases metabolize polyunsaturated fatty acids into signalling molecules such as leukotrienes and lipoxins. 15-lipoxygenase-1 (15-LOX-1) is an important mammalian lipoxygenase and plays a crucial regulatory role in several respiratory diseases such as asthma, COPD and chronic bronchitis. Novel potent and selective inhibitors of 15-LOX-1 are required to explore the role of this enzyme in drug discovery. In this study we describe structure activity relationships for 6-benzyloxysalicylates as inhibitors of human 15-LOX-1. Kinetic analysis suggests competitive inhibition and the binding model of these compounds can be rationalized using molecular modelling studies. The most potent derivative 37a shows a Ki value of 1.7 μM. These structure activity relationships provide a basis to design improved inhibitors and to explore 15-LOX-1 as a drug target.
authors.affiliation: Department of Pharmaceutical Gene Modulation, Groningen Research Institute of Pharmacy, University of Groningen, Antonius Deusinglaan 1, 9713 AV Groningen, The Netherlands.
authors.forename: Nikolaos
authors.initials: N
authors.lastname: Eleftheriadis
authors.affiliation: Department of Pharmaceutical Gene Modulation, Groningen Research Institute of Pharmacy, University of Groningen, Antonius Deusinglaan 1, 9713 AV Groningen, The Netherlands.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Thee
authors.affiliation: Department of Pharmaceutical Gene Modulation, Groningen Research Institute of Pharmacy, University of Groningen, Antonius Deusinglaan 1, 9713 AV Groningen, The Netherlands.
authors.forename: Johan
authors.initials: J
authors.lastname: te Biesebeek
authors.affiliation: Department of Pharmaceutical Gene Modulation, Groningen Research Institute of Pharmacy, University of Groningen, Antonius Deusinglaan 1, 9713 AV Groningen, The Netherlands.
authors.forename: Petra
authors.initials: P
authors.lastname: van der Wouden
authors.affiliation: Department of Pharmaceutical Biology, Groningen Research Institute of Pharmacy, University of Groningen, Antonius Deusinglaan 1, 9713 AV Groningen, The Netherlands.
authors.forename: Bert-Jan
authors.initials: BJ
authors.lastname: Baas
authors.affiliation: Department of Pharmaceutical Gene Modulation, Groningen Research Institute of Pharmacy, University of Groningen, Antonius Deusinglaan 1, 9713 AV Groningen, The Netherlands. Electronic address: f.j.dekker@rug.nl.
authors.forename: Frank J
authors.initials: FJ
authors.lastname: Dekker
mesh_terms: D001093:Arachidonate 15-Lipoxygenase / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007700:Kinetics; D016859:Lipoxygenase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D008958:Models, Molecular; D015394:Molecular Structure; D012459:Salicylates / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: C000603761:2-((4-((3,7-dimethyloctyl)oxy)benzyl)oxy)-6-hydroxybenzoic acid; D016859:Lipoxygenase Inhibitors; D012459:Salicylates; C515716:ALOX15 protein, human; D001093:Arachidonate 15-Lipoxygenase
keywords: Enzyme kinetics; Expression; Inhibitor; Lipoxygenase; Salicylate