Cargando…
Potential Moracin M Prodrugs Strongly Attenuate Airway Inflammation In Vivo
This study aims to develop new potential therapeutic moracin M prodrugs acting on lung inflammatory disorders. Potential moracin M prodrugs (KW01-KW07) were chemically synthesized to obtain potent orally active derivatives, and their pharmacological activities against lung inflammation were, for the...
Autores principales: | , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
The Korean Society of Applied Pharmacology
2020
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7327141/ https://www.ncbi.nlm.nih.gov/pubmed/32388942 http://dx.doi.org/10.4062/biomolther.2019.212 |
_version_ | 1783552481151680512 |
---|---|
author | Lee, Jongkook Mandava, Suresh Ahn, Sung-Hoon Bae, Myung-Ae So, Kyung Soo Kwon, Ki Sun Kim, Hyun Pyo |
author_facet | Lee, Jongkook Mandava, Suresh Ahn, Sung-Hoon Bae, Myung-Ae So, Kyung Soo Kwon, Ki Sun Kim, Hyun Pyo |
author_sort | Lee, Jongkook |
collection | PubMed |
description | This study aims to develop new potential therapeutic moracin M prodrugs acting on lung inflammatory disorders. Potential moracin M prodrugs (KW01-KW07) were chemically synthesized to obtain potent orally active derivatives, and their pharmacological activities against lung inflammation were, for the first time, examined in vivo using lipopolysaccharide (LPS)-induced acute lung injury model. In addition, the metabolism of KW02 was also investigated using microsomal stability test and pharmacokinetic study in rats. When orally administered, some of these compounds (30 mg/kg) showed higher inhibitory action against LPS-induced lung inflammation in mice compared to moracin M. Of them, 2-(3,5-bis((dimethylcarbamoyl)oxy)phenyl)benzofuran-6-yl acetate (KW02) showed potent and dose-dependent inhibitory effect on the same animal model of lung inflammation at 1, 3, and 10 mg/kg. This compound at 10 mg/kg also significantly reduced IL-1β concentration in the bronchoalveolar lavage fluid of the inflamed-lungs. KW02 was rapidly metabolized to 5-(6-hydroxybenzofuran-2-yl)-1,3-phenylene bis(dimethylcarbamate) (KW06) and moracin M when it was incubated with rat serum and liver microsome as expected. When KW02 was administered to rats via intravenous or oral route, KW06 was detected in the serum as a metabolite. Thus, it is concluded that KW02 has potent inhibitory action against LPS-induced lung inflammation. It could behave as a potential prodrug of moracin M to effectively treat lung inflammatory disorders. |
format | Online Article Text |
id | pubmed-7327141 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | The Korean Society of Applied Pharmacology |
record_format | MEDLINE/PubMed |
spelling | pubmed-73271412020-07-01 Potential Moracin M Prodrugs Strongly Attenuate Airway Inflammation In Vivo Lee, Jongkook Mandava, Suresh Ahn, Sung-Hoon Bae, Myung-Ae So, Kyung Soo Kwon, Ki Sun Kim, Hyun Pyo Biomol Ther (Seoul) Original Article This study aims to develop new potential therapeutic moracin M prodrugs acting on lung inflammatory disorders. Potential moracin M prodrugs (KW01-KW07) were chemically synthesized to obtain potent orally active derivatives, and their pharmacological activities against lung inflammation were, for the first time, examined in vivo using lipopolysaccharide (LPS)-induced acute lung injury model. In addition, the metabolism of KW02 was also investigated using microsomal stability test and pharmacokinetic study in rats. When orally administered, some of these compounds (30 mg/kg) showed higher inhibitory action against LPS-induced lung inflammation in mice compared to moracin M. Of them, 2-(3,5-bis((dimethylcarbamoyl)oxy)phenyl)benzofuran-6-yl acetate (KW02) showed potent and dose-dependent inhibitory effect on the same animal model of lung inflammation at 1, 3, and 10 mg/kg. This compound at 10 mg/kg also significantly reduced IL-1β concentration in the bronchoalveolar lavage fluid of the inflamed-lungs. KW02 was rapidly metabolized to 5-(6-hydroxybenzofuran-2-yl)-1,3-phenylene bis(dimethylcarbamate) (KW06) and moracin M when it was incubated with rat serum and liver microsome as expected. When KW02 was administered to rats via intravenous or oral route, KW06 was detected in the serum as a metabolite. Thus, it is concluded that KW02 has potent inhibitory action against LPS-induced lung inflammation. It could behave as a potential prodrug of moracin M to effectively treat lung inflammatory disorders. The Korean Society of Applied Pharmacology 2020-07-01 2020-05-11 /pmc/articles/PMC7327141/ /pubmed/32388942 http://dx.doi.org/10.4062/biomolther.2019.212 Text en Copyright © 2020, The Korean Society of Applied Pharmacology This is an open-access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Original Article Lee, Jongkook Mandava, Suresh Ahn, Sung-Hoon Bae, Myung-Ae So, Kyung Soo Kwon, Ki Sun Kim, Hyun Pyo Potential Moracin M Prodrugs Strongly Attenuate Airway Inflammation In Vivo |
title | Potential Moracin M Prodrugs Strongly Attenuate Airway Inflammation In Vivo |
title_full | Potential Moracin M Prodrugs Strongly Attenuate Airway Inflammation In Vivo |
title_fullStr | Potential Moracin M Prodrugs Strongly Attenuate Airway Inflammation In Vivo |
title_full_unstemmed | Potential Moracin M Prodrugs Strongly Attenuate Airway Inflammation In Vivo |
title_short | Potential Moracin M Prodrugs Strongly Attenuate Airway Inflammation In Vivo |
title_sort | potential moracin m prodrugs strongly attenuate airway inflammation in vivo |
topic | Original Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7327141/ https://www.ncbi.nlm.nih.gov/pubmed/32388942 http://dx.doi.org/10.4062/biomolther.2019.212 |
work_keys_str_mv | AT leejongkook potentialmoracinmprodrugsstronglyattenuateairwayinflammationinvivo AT mandavasuresh potentialmoracinmprodrugsstronglyattenuateairwayinflammationinvivo AT ahnsunghoon potentialmoracinmprodrugsstronglyattenuateairwayinflammationinvivo AT baemyungae potentialmoracinmprodrugsstronglyattenuateairwayinflammationinvivo AT sokyungsoo potentialmoracinmprodrugsstronglyattenuateairwayinflammationinvivo AT kwonkisun potentialmoracinmprodrugsstronglyattenuateairwayinflammationinvivo AT kimhyunpyo potentialmoracinmprodrugsstronglyattenuateairwayinflammationinvivo |