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Movement to the Clinic of Soluble Epoxide Hydrolase Inhibitor EC5026 as an Analgesic for Neuropathic Pain and for Use as a Nonaddictive Opioid Alternative

[Image: see text] This report describes the development of an orally active analgesic that resolves inflammation and neuropathic pain without the addictive potential of opioids. EC5026 acts on the cytochrome P450 branch of the arachidonate cascade to stabilize epoxides of polyunsaturated fatty acids...

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Autores principales: Hammock, Bruce D., McReynolds, Cindy B., Wagner, Karen, Buckpitt, Alan, Cortes-Puch, Irene, Croston, Glenn, Lee, Kin Sing Stephen, Yang, Jun, Schmidt, William K., Hwang, Sung Hee
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Chemical Society 2021
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7917437/
https://www.ncbi.nlm.nih.gov/pubmed/33550801
http://dx.doi.org/10.1021/acs.jmedchem.0c01886
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author Hammock, Bruce D.
McReynolds, Cindy B.
Wagner, Karen
Buckpitt, Alan
Cortes-Puch, Irene
Croston, Glenn
Lee, Kin Sing Stephen
Yang, Jun
Schmidt, William K.
Hwang, Sung Hee
author_facet Hammock, Bruce D.
McReynolds, Cindy B.
Wagner, Karen
Buckpitt, Alan
Cortes-Puch, Irene
Croston, Glenn
Lee, Kin Sing Stephen
Yang, Jun
Schmidt, William K.
Hwang, Sung Hee
author_sort Hammock, Bruce D.
collection PubMed
description [Image: see text] This report describes the development of an orally active analgesic that resolves inflammation and neuropathic pain without the addictive potential of opioids. EC5026 acts on the cytochrome P450 branch of the arachidonate cascade to stabilize epoxides of polyunsaturated fatty acids (EpFA), which are natural mediators that reduce pain, resolve inflammation, and maintain normal blood pressure. EC5026 is a slow-tight binding transition-state mimic that inhibits the soluble epoxide hydrolase (sEH) at picomolar concentrations. The sEH rapidly degrades EpFA; thus, inhibiting sEH increases EpFA in vivo and confers beneficial effects. This mechanism addresses disease states by shifting endoplasmic reticulum stress from promoting cellular senescence and inflammation toward cell survival and homeostasis. We describe the synthesis and optimization of EC5026 and its development through human Phase 1a trials with no drug-related adverse events. Additionally, we outline fundamental work leading to discovery of the analgesic and inflammation-resolving CYP450 branch of the arachidonate cascade.
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spelling pubmed-79174372021-03-02 Movement to the Clinic of Soluble Epoxide Hydrolase Inhibitor EC5026 as an Analgesic for Neuropathic Pain and for Use as a Nonaddictive Opioid Alternative Hammock, Bruce D. McReynolds, Cindy B. Wagner, Karen Buckpitt, Alan Cortes-Puch, Irene Croston, Glenn Lee, Kin Sing Stephen Yang, Jun Schmidt, William K. Hwang, Sung Hee J Med Chem [Image: see text] This report describes the development of an orally active analgesic that resolves inflammation and neuropathic pain without the addictive potential of opioids. EC5026 acts on the cytochrome P450 branch of the arachidonate cascade to stabilize epoxides of polyunsaturated fatty acids (EpFA), which are natural mediators that reduce pain, resolve inflammation, and maintain normal blood pressure. EC5026 is a slow-tight binding transition-state mimic that inhibits the soluble epoxide hydrolase (sEH) at picomolar concentrations. The sEH rapidly degrades EpFA; thus, inhibiting sEH increases EpFA in vivo and confers beneficial effects. This mechanism addresses disease states by shifting endoplasmic reticulum stress from promoting cellular senescence and inflammation toward cell survival and homeostasis. We describe the synthesis and optimization of EC5026 and its development through human Phase 1a trials with no drug-related adverse events. Additionally, we outline fundamental work leading to discovery of the analgesic and inflammation-resolving CYP450 branch of the arachidonate cascade. American Chemical Society 2021-02-07 2021-02-25 /pmc/articles/PMC7917437/ /pubmed/33550801 http://dx.doi.org/10.1021/acs.jmedchem.0c01886 Text en © 2021 American Chemical Society Permits non-commercial access and re-use, provided that author attribution and integrity are maintained; but does not permit creation of adaptations or other derivative works (https://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Hammock, Bruce D.
McReynolds, Cindy B.
Wagner, Karen
Buckpitt, Alan
Cortes-Puch, Irene
Croston, Glenn
Lee, Kin Sing Stephen
Yang, Jun
Schmidt, William K.
Hwang, Sung Hee
Movement to the Clinic of Soluble Epoxide Hydrolase Inhibitor EC5026 as an Analgesic for Neuropathic Pain and for Use as a Nonaddictive Opioid Alternative
title Movement to the Clinic of Soluble Epoxide Hydrolase Inhibitor EC5026 as an Analgesic for Neuropathic Pain and for Use as a Nonaddictive Opioid Alternative
title_full Movement to the Clinic of Soluble Epoxide Hydrolase Inhibitor EC5026 as an Analgesic for Neuropathic Pain and for Use as a Nonaddictive Opioid Alternative
title_fullStr Movement to the Clinic of Soluble Epoxide Hydrolase Inhibitor EC5026 as an Analgesic for Neuropathic Pain and for Use as a Nonaddictive Opioid Alternative
title_full_unstemmed Movement to the Clinic of Soluble Epoxide Hydrolase Inhibitor EC5026 as an Analgesic for Neuropathic Pain and for Use as a Nonaddictive Opioid Alternative
title_short Movement to the Clinic of Soluble Epoxide Hydrolase Inhibitor EC5026 as an Analgesic for Neuropathic Pain and for Use as a Nonaddictive Opioid Alternative
title_sort movement to the clinic of soluble epoxide hydrolase inhibitor ec5026 as an analgesic for neuropathic pain and for use as a nonaddictive opioid alternative
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7917437/
https://www.ncbi.nlm.nih.gov/pubmed/33550801
http://dx.doi.org/10.1021/acs.jmedchem.0c01886
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