title: Design of a novel thiophene inhibitor of 15-lipoxygenase-1 with both anti-inflammatory and neuroprotective properties.
abstract: The enzyme 15-lipoxygenase-1 (15-LOX-1) plays a dual role in diseases with an inflammatory component. On one hand 15-LOX-1 plays a role in pro-inflammatory gene expression and on the other hand it has been shown to be involved in central nervous system (CNS) disorders by its ability to mediate oxidative stress and damage of mitochondrial membranes under hypoxic conditions. In order to further explore applications in the CNS, novel 15-LOX-1 inhibitors with favorable physicochemical properties need to be developed. Here, we present Substitution Oriented Screening (SOS) in combination with Multi Component Chemistry (MCR) as an effective strategy to identify a diversely substituted small heterocyclic inhibitors for 15-LOX-1, denoted ThioLox, with physicochemical properties superior to previously identified inhibitors. Ex vivo biological evaluation in precision-cut lung slices (PCLS) showed inhibition of pro-inflammatory gene expression and in vitro studies on neuronal HT-22 cells showed a strong protection against glutamate toxicity for this 15-LOX-1 inhibitor. This provides a novel approach to identify novel small with favorable physicochemical properties for exploring 15-LOX-1 as a drug target in inflammatory diseases and neurodegeneration.
authors.affiliation: Department of Chemical and Pharmaceutical Biology, Groningen Research Institute of Pharmacy, University of Groningen, Groningen, 9713 AV, The Netherlands.
authors.forename: Nikolaos
authors.initials: N
authors.lastname: Eleftheriadis
authors.affiliation: Department of Chemical and Pharmaceutical Biology, Groningen Research Institute of Pharmacy, University of Groningen, Groningen, 9713 AV, The Netherlands.
authors.forename: Hessel
authors.initials: H
authors.lastname: Poelman
authors.affiliation: Department of Chemical and Pharmaceutical Biology, Groningen Research Institute of Pharmacy, University of Groningen, Groningen, 9713 AV, The Netherlands.
authors.forename: Niek G J
authors.initials: NGJ
authors.lastname: Leus
authors.affiliation: Institute of Pharmacology and Clinical Pharmacy, Philipps-University Marburg, Marburg, Germany.
authors.forename: Birgit
authors.initials: B
authors.lastname: Honrath
authors.affiliation: Department of Drug Design, Groningen Research Institute of Pharmacy, University of Groningen, Groningen, 9713 AV, The Netherlands.
authors.forename: Constantinos G
authors.initials: CG
authors.lastname: Neochoritis
authors.affiliation: Department of Molecular Pharmacology, Groningen Research Institute of Pharmacy, University of Groningen, Groningen, 9713 AV, The Netherlands.
authors.forename: Amalia
authors.initials: A
authors.lastname: Dolga
authors.affiliation: Department of Drug Design, Groningen Research Institute of Pharmacy, University of Groningen, Groningen, 9713 AV, The Netherlands.
authors.forename: Alexander
authors.initials: A
authors.lastname: Dömling
authors.affiliation: Department of Chemical and Pharmaceutical Biology, Groningen Research Institute of Pharmacy, University of Groningen, Groningen, 9713 AV, The Netherlands.
authors.forename: Frank J
authors.initials: FJ
authors.lastname: Dekker
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D008084:Lipoxygenase / Q000737:chemistry / Q000378:metabolism*; D016859:Lipoxygenase Inhibitors / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D051379:Mice; D018696:Neuroprotective Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D013876:Thiophenes / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D000893:Anti-Inflammatory Agents; D016859:Lipoxygenase Inhibitors; D018696:Neuroprotective Agents; D013876:Thiophenes; D008084:Lipoxygenase
keywords: 15-Lipoxygenase; Inflammation; Multi component chemistry; Neurodegeneration; Substitution Oriented Screening; Thiophene-based inhibitor