PMID- 27477687
OWN - NLM
STAT- MEDLINE
DCOM- 20170222
LR  - 20220129
IS  - 1768-3254 (Electronic)
IS  - 0223-5234 (Print)
IS  - 0223-5234 (Linking)
VI  - 122
DP  - 2016 Oct 21
TI  - Design of a novel thiophene inhibitor of 15-lipoxygenase-1 with both 
      anti-inflammatory and neuroprotective properties.
PG  - 786-801
LID - 10.1016/j.ejmech.2016.07.010 [doi]
AB  - 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.
CI  - Copyright (c) 2016 Elsevier Masson SAS. All rights reserved.
FAU - Eleftheriadis, Nikolaos
AU  - Eleftheriadis N
AD  - Department of Chemical and Pharmaceutical Biology, Groningen Research Institute 
      of Pharmacy, University of Groningen, Groningen, 9713 AV, The Netherlands.
FAU - Poelman, Hessel
AU  - Poelman H
AD  - Department of Chemical and Pharmaceutical Biology, Groningen Research Institute 
      of Pharmacy, University of Groningen, Groningen, 9713 AV, The Netherlands.
FAU - Leus, Niek G J
AU  - Leus NGJ
AD  - Department of Chemical and Pharmaceutical Biology, Groningen Research Institute 
      of Pharmacy, University of Groningen, Groningen, 9713 AV, The Netherlands.
FAU - Honrath, Birgit
AU  - Honrath B
AD  - Institute of Pharmacology and Clinical Pharmacy, Philipps-University Marburg, 
      Marburg, Germany.
FAU - Neochoritis, Constantinos G
AU  - Neochoritis CG
AD  - Department of Drug Design, Groningen Research Institute of Pharmacy, University 
      of Groningen, Groningen, 9713 AV, The Netherlands.
FAU - Dolga, Amalia
AU  - Dolga A
AD  - Department of Molecular Pharmacology, Groningen Research Institute of Pharmacy, 
      University of Groningen, Groningen, 9713 AV, The Netherlands.
FAU - Domling, Alexander
AU  - Domling A
AD  - Department of Drug Design, Groningen Research Institute of Pharmacy, University 
      of Groningen, Groningen, 9713 AV, The Netherlands.
FAU - Dekker, Frank J
AU  - Dekker FJ
AD  - Department of Chemical and Pharmaceutical Biology, Groningen Research Institute 
      of Pharmacy, University of Groningen, Groningen, 9713 AV, The Netherlands.
LA  - eng
GR  - 309782/ERC_/European Research Council/International
GR  - R01 GM097082/GM/NIGMS NIH HHS/United States
PT  - Journal Article
DEP - 20160709
PL  - France
TA  - Eur J Med Chem
JT  - European journal of medicinal chemistry
JID - 0420510
RN  - 0 (Anti-Inflammatory Agents)
RN  - 0 (Lipoxygenase Inhibitors)
RN  - 0 (Neuroprotective Agents)
RN  - 0 (Thiophenes)
RN  - EC 1.13.11.12 (Lipoxygenase)
SB  - IM
MH  - Animals
MH  - Anti-Inflammatory Agents/chemistry/metabolism/*pharmacology
MH  - Cell Line
MH  - Dose-Response Relationship, Drug
MH  - Lipoxygenase/chemistry/*metabolism
MH  - Lipoxygenase Inhibitors/chemistry/metabolism/*pharmacology
MH  - Mice
MH  - Neuroprotective Agents/chemistry/metabolism/*pharmacology
MH  - Thiophenes/chemistry/metabolism/*pharmacology
PMC - PMC5010146
MID - EMS69733
OID - NLM: EMS69733
OTO - NOTNLM
OT  - 15-Lipoxygenase
OT  - Inflammation
OT  - Multi component chemistry
OT  - Neurodegeneration
OT  - Substitution Oriented Screening
OT  - Thiophene-based inhibitor
EDAT- 2016/08/02 06:00
MHDA- 2017/02/23 06:00
PMCR- 2016/10/21
CRDT- 2016/08/02 06:00
PHST- 2016/05/20 00:00 [received]
PHST- 2016/07/05 00:00 [revised]
PHST- 2016/07/07 00:00 [accepted]
PHST- 2016/08/02 06:00 [entrez]
PHST- 2016/08/02 06:00 [pubmed]
PHST- 2017/02/23 06:00 [medline]
PHST- 2016/10/21 00:00 [pmc-release]
AID - S0223-5234(16)30558-X [pii]
AID - 10.1016/j.ejmech.2016.07.010 [doi]
PST - ppublish
SO  - Eur J Med Chem. 2016 Oct 21;122:786-801. doi: 10.1016/j.ejmech.2016.07.010. Epub 
      2016 Jul 9.