PMID- 32240653
OWN - NLM
STAT- MEDLINE
DCOM- 20201225
LR  - 20231121
IS  - 1873-2968 (Electronic)
IS  - 0006-2952 (Print)
IS  - 0006-2952 (Linking)
VI  - 179
DP  - 2020 Sep
TI  - Targeting the OXE receptor as a potential novel therapy for asthma.
PG  - 113930
LID - S0006-2952(20)30158-1 [pii]
LID - 10.1016/j.bcp.2020.113930 [doi]
AB  - 5-Oxo-6,8,11,14-eicosatetraenoic acid (5-oxo-ETE) is an arachidonic acid 
      metabolite formed by oxidation of the 5-lipoxygenase (5-LO) product 
      5S-hydroxy-6,8,11,14-eicosatetraenoic acid (5S-HETE) by the NADP(+)-dependent 
      enzyme 5-hydroxyeicosanoid dehydrogenase. It is the only 5-LO product with 
      appreciable chemoattractant activity for human eosinophils. Its actions are 
      mediated by the selective OXE receptor, which is highly expressed on eosinophils, 
      basophils, neutrophils and monocytes. Orthologs of the OXER1 gene, which encodes 
      this receptor, are found in many species except for rodents. Intradermal 
      injection of 5-oxo-ETE into humans and monkeys elicits eosinophil infiltration 
      into the skin, raising the possibility that it may play a pathophysiological role 
      in eosinophilic diseases. To investigate this and possibly identify a novel 
      therapy we sought to prepare synthetic antagonists that could selectively block 
      the OXE receptor. We synthesized a series of indole-based compounds bearing 
      substituents that mimic the regions of 5-oxo-ETE that are required for biological 
      activity, which we modified to reduce metabolism. The most potent of these OXE 
      receptor antagonists is S-Y048, which is a potent inhibitor of 5-oxo-ETE-induced 
      calcium mobilization (IC(50), 20 pM) and has a long half-life following oral 
      administration. S-Y048 inhibited allergen-induced eosinophil infiltration into 
      the skin of rhesus monkeys that had been experimentally sensitized to house dust 
      mite and inhibited pulmonary inflammation resulting from challenge with 
      aerosolized allergen. These data provide the first evidence for a 
      pathophysiological role for 5-oxo-ETE in mammals and suggest that potent and 
      selective OXE receptor antagonists such as S-Y048 may be useful therapeutic 
      agents in asthma and other eosinophilic diseases.
CI  - Copyright (c) 2020 Elsevier Inc. All rights reserved.
FAU - Powell, William S
AU  - Powell WS
AD  - Meakins-Christie Laboratories, Centre for Translational Biology, McGill 
      University Health Centre, 1001 Decarie Blvd, Montreal, QC H4A 3J1, Canada. 
      Electronic address: william.powell@mcgill.ca.
FAU - Rokach, Joshua
AU  - Rokach J
AD  - Claude Pepper Institute and Department of Chemistry, Florida Institute of 
      Technology, 150 West University Boulevard, Melbourne, FL 32901-6982, USA.
LA  - eng
GR  - R01 HL081873/HL/NHLBI NIH HHS/United States
GR  - PP2-133388/CAPMC/CIHR/Canada
GR  - MOP-6254/CAPMC/CIHR/Canada
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PT  - Review
DEP - 20200330
PL  - England
TA  - Biochem Pharmacol
JT  - Biochemical pharmacology
JID - 0101032
RN  - 0 (5-oxo-eicosatetraenoic acid)
RN  - 0 (Anti-Asthmatic Agents)
RN  - 0 (Arachidonic Acids)
RN  - 0 (OXER1 protein, human)
RN  - 0 (Receptors, Eicosanoid)
RN  - 83869-56-1 (Granulocyte-Macrophage Colony-Stimulating Factor)
SB  - IM
MH  - Animals
MH  - Anti-Asthmatic Agents/chemical synthesis/chemistry/*pharmacology
MH  - Arachidonic Acids/*metabolism/pharmacology
MH  - Asthma/*drug therapy/*metabolism
MH  - Basement Membrane/drug effects/metabolism
MH  - Disease Models, Animal
MH  - Eosinophils/drug effects/metabolism
MH  - Granulocyte-Macrophage Colony-Stimulating Factor/metabolism/pharmacology
MH  - Humans
MH  - Lipid Peroxidation
MH  - Molecular Targeted Therapy/methods
MH  - Neutrophils/drug effects/metabolism
MH  - Receptors, Eicosanoid/antagonists & inhibitors/*metabolism
MH  - Structure-Activity Relationship
PMC - PMC10656995
MID - NIHMS1580550
OTO - NOTNLM
OT  - 5-Lipoxygenase products
OT  - 5-Oxo-ETE
OT  - Allergy
OT  - Inflammation
OT  - OXE receptor antagonists
COIS- Potential conflict of interest W.S.P. and J.R. have been granted a patent 
      covering S-230 and have applied for a patent covering S-C025 and S-Y048.
EDAT- 2020/04/03 06:00
MHDA- 2020/12/29 06:00
PMCR- 2023/11/18
CRDT- 2020/04/03 06:00
PHST- 2020/02/17 00:00 [received]
PHST- 2020/03/19 00:00 [accepted]
PHST- 2020/04/03 06:00 [pubmed]
PHST- 2020/12/29 06:00 [medline]
PHST- 2020/04/03 06:00 [entrez]
PHST- 2023/11/18 00:00 [pmc-release]
AID - S0006-2952(20)30158-1 [pii]
AID - 10.1016/j.bcp.2020.113930 [doi]
PST - ppublish
SO  - Biochem Pharmacol. 2020 Sep;179:113930. doi: 10.1016/j.bcp.2020.113930. Epub 2020 
      Mar 30.