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Targeting the OXE receptor as a potential novel therapy for asthma.
- Source :
-
Biochemical pharmacology [Biochem Pharmacol] 2020 Sep; Vol. 179, pp. 113930. Date of Electronic Publication: 2020 Mar 30. - Publication Year :
- 2020
-
Abstract
- 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 <superscript>+</superscript> -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 <subscript>50</subscript> , 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.<br /> (Copyright © 2020 Elsevier Inc. All rights reserved.)
- Subjects :
- Animals
Anti-Asthmatic Agents chemical synthesis
Anti-Asthmatic Agents chemistry
Arachidonic Acids pharmacology
Basement Membrane drug effects
Basement Membrane metabolism
Disease Models, Animal
Eosinophils drug effects
Eosinophils metabolism
Granulocyte-Macrophage Colony-Stimulating Factor metabolism
Granulocyte-Macrophage Colony-Stimulating Factor pharmacology
Humans
Lipid Peroxidation
Molecular Targeted Therapy methods
Neutrophils drug effects
Neutrophils metabolism
Receptors, Eicosanoid antagonists & inhibitors
Structure-Activity Relationship
Anti-Asthmatic Agents pharmacology
Arachidonic Acids metabolism
Asthma drug therapy
Asthma metabolism
Receptors, Eicosanoid metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1873-2968
- Volume :
- 179
- Database :
- MEDLINE
- Journal :
- Biochemical pharmacology
- Publication Type :
- Academic Journal
- Accession number :
- 32240653
- Full Text :
- https://doi.org/10.1016/j.bcp.2020.113930