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Discovery of Uracil Derivatives as Potent Inhibitors of Fatty Acid Amide Hydrolase
Fatty Acid Amide Hydrolase (FAAH) is an intracellular serine enzyme involved in the biological degradation of the fatty acid ethanolamide family of signaling lipids, which exerts neuroprotective, anti-inflammatory, and analgesic properties. In the present study, a conjugated 2,4-dioxo-pyrimidine-1-c...
Autores principales: | , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2016
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6274076/ https://www.ncbi.nlm.nih.gov/pubmed/26901181 http://dx.doi.org/10.3390/molecules21020229 |
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author | Qiu, Yan Zhang, Yang Li, Yuhang Ren, Jie |
author_facet | Qiu, Yan Zhang, Yang Li, Yuhang Ren, Jie |
author_sort | Qiu, Yan |
collection | PubMed |
description | Fatty Acid Amide Hydrolase (FAAH) is an intracellular serine enzyme involved in the biological degradation of the fatty acid ethanolamide family of signaling lipids, which exerts neuroprotective, anti-inflammatory, and analgesic properties. In the present study, a conjugated 2,4-dioxo-pyrimidine-1-carboxamide scaffold was confirmed as a novel template for FAAH inhibitors, based on which, a series of analogues had been prepared for an initial structure-activity relationship (SAR) study. Most of the synthesized compounds displayed moderate to significant FAAH inhibitory potency. Among them, compounds 11 and 14 showed better activity than others, with IC(50) values of 21 and 53 nM. SAR analysis indicated that 2,4-dioxopyrimidine-1-carboxamides represented a novel class of potent inhibitors of FAAH, and substitution at the uracil ring or replacement of the N-terminal group might favor the inhibitory potency. Selected compounds of this class may be used as useful parent molecules for further investigation. |
format | Online Article Text |
id | pubmed-6274076 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-62740762018-12-28 Discovery of Uracil Derivatives as Potent Inhibitors of Fatty Acid Amide Hydrolase Qiu, Yan Zhang, Yang Li, Yuhang Ren, Jie Molecules Communication Fatty Acid Amide Hydrolase (FAAH) is an intracellular serine enzyme involved in the biological degradation of the fatty acid ethanolamide family of signaling lipids, which exerts neuroprotective, anti-inflammatory, and analgesic properties. In the present study, a conjugated 2,4-dioxo-pyrimidine-1-carboxamide scaffold was confirmed as a novel template for FAAH inhibitors, based on which, a series of analogues had been prepared for an initial structure-activity relationship (SAR) study. Most of the synthesized compounds displayed moderate to significant FAAH inhibitory potency. Among them, compounds 11 and 14 showed better activity than others, with IC(50) values of 21 and 53 nM. SAR analysis indicated that 2,4-dioxopyrimidine-1-carboxamides represented a novel class of potent inhibitors of FAAH, and substitution at the uracil ring or replacement of the N-terminal group might favor the inhibitory potency. Selected compounds of this class may be used as useful parent molecules for further investigation. MDPI 2016-02-18 /pmc/articles/PMC6274076/ /pubmed/26901181 http://dx.doi.org/10.3390/molecules21020229 Text en © 2016 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons by Attribution (CC-BY) license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Communication Qiu, Yan Zhang, Yang Li, Yuhang Ren, Jie Discovery of Uracil Derivatives as Potent Inhibitors of Fatty Acid Amide Hydrolase |
title | Discovery of Uracil Derivatives as Potent Inhibitors of Fatty Acid Amide Hydrolase |
title_full | Discovery of Uracil Derivatives as Potent Inhibitors of Fatty Acid Amide Hydrolase |
title_fullStr | Discovery of Uracil Derivatives as Potent Inhibitors of Fatty Acid Amide Hydrolase |
title_full_unstemmed | Discovery of Uracil Derivatives as Potent Inhibitors of Fatty Acid Amide Hydrolase |
title_short | Discovery of Uracil Derivatives as Potent Inhibitors of Fatty Acid Amide Hydrolase |
title_sort | discovery of uracil derivatives as potent inhibitors of fatty acid amide hydrolase |
topic | Communication |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6274076/ https://www.ncbi.nlm.nih.gov/pubmed/26901181 http://dx.doi.org/10.3390/molecules21020229 |
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