Inhibition of LPS-Induced PGE<sub>2</sub> Production by Arylsulfonamide Derivatives via the Selective Inhibition of mPGES-1 Enzyme

Inhibition of LPS-Induced PGE<sub>2</sub> Production by Arylsulfonamide Derivatives via the Selective Inhibition of mPGES-1 Enzyme

Microsomal prostaglandin E synthase-1 (mPGES-1) is responsible for the massive prostaglandin E<sub>2</sub> (PGE<sub>2</sub>) formation during inflammation. Increasing evidence reveals mPGES-1 inhibitors as a safe alternative to nonsteroidal anti-inflammatory drugs. Recently,...

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Main Authors: Misong Kim, Changyoung Jang, Yunchan Nam, Kyung-Tae Lee, Jaeyeol Lee
Format: Article
Language:English
Published: MDPI AG 2019-08-01
Series:Proceedings
Subjects:
mPGES-1
inflammation
arylsulfonamides
Online Access:https://www.mdpi.com/2504-3900/22/1/37
id doaj-328177c7897c4329853f6de3276e9640
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spelling doaj-328177c7897c4329853f6de3276e96402020-11-25T00:56:29ZengMDPI AGProceedings2504-39002019-08-012213710.3390/proceedings2019022037proceedings2019022037Inhibition of LPS-Induced PGE<sub>2</sub> Production by Arylsulfonamide Derivatives via the Selective Inhibition of mPGES-1 EnzymeMisong Kim0Changyoung Jang1Yunchan Nam2Kyung-Tae Lee3Jaeyeol Lee4Research Institute for Basic Sciences and Department of Chemistry, College of Sciences, Kyung Hee University, Seoul 02447, KoreaResearch Institute for Basic Sciences and Department of Chemistry, College of Sciences, Kyung Hee University, Seoul 02447, KoreaResearch Institute for Basic Sciences and Department of Chemistry, College of Sciences, Kyung Hee University, Seoul 02447, KoreaDepartment of Life and Nanopharmaceutical Science, Kyung Hee University, Seoul 02447, KoreaResearch Institute for Basic Sciences and Department of Chemistry, College of Sciences, Kyung Hee University, Seoul 02447, KoreaMicrosomal prostaglandin E synthase-1 (mPGES-1) is responsible for the massive prostaglandin E<sub>2</sub> (PGE<sub>2</sub>) formation during inflammation. Increasing evidence reveals mPGES-1 inhibitors as a safe alternative to nonsteroidal anti-inflammatory drugs. Recently, we reported that a novel series of phenylsulfonyl hydrazide derivatives could reduce LPS-induced PGE<sub>2</sub> levels in RAW 264.7 macrophage cells via an inhibition of the mPGES-1 enzyme. However, a few of the phenylsulfonyl hydrazide derivatives showed poor metabolic stability in liver microsomes. In order to identify new mPGES-1 inhibitors with improved metabolic stability, therefore, a series of arylsulfonamide derivatives has been synthesized and biologically evaluated against PGE<sub>2</sub> production and the mPGES-1 enzyme. Among them, MPO-0186 inhibits the production of PGE<sub>2</sub> (IC<sub>50</sub> = 0.20 &#956;M) in A549 cells via inhibition of mPGES-1 (IC<sub>50</sub> = 0.49 &#956;M in a cell-free assay) together with high selectivity over both COX-1 and COX-2. A molecular docking study theoretically suggests that MPO-0186 could inhibit PGE<sub>2</sub> production by blocking the PGH<sub>2</sub> binding site of the mPGES-1 enzyme. Furthermore, MPO-0186 demonstrated good metabolic stability in human liver microsomes and no significant inhibition observed in clinically relevant CYP isoforms.https://www.mdpi.com/2504-3900/22/1/37mPGES-1inflammationarylsulfonamides
collection DOAJ
language English
format Article
sources DOAJ
author Misong Kim
Changyoung Jang
Yunchan Nam
Kyung-Tae Lee
Jaeyeol Lee
spellingShingle Misong Kim
Changyoung Jang
Yunchan Nam
Kyung-Tae Lee
Jaeyeol Lee
Inhibition of LPS-Induced PGE<sub>2</sub> Production by Arylsulfonamide Derivatives via the Selective Inhibition of mPGES-1 Enzyme
Proceedings
mPGES-1
inflammation
arylsulfonamides
author_facet Misong Kim
Changyoung Jang
Yunchan Nam
Kyung-Tae Lee
Jaeyeol Lee
author_sort Misong Kim
title Inhibition of LPS-Induced PGE<sub>2</sub> Production by Arylsulfonamide Derivatives via the Selective Inhibition of mPGES-1 Enzyme
title_short Inhibition of LPS-Induced PGE<sub>2</sub> Production by Arylsulfonamide Derivatives via the Selective Inhibition of mPGES-1 Enzyme
title_full Inhibition of LPS-Induced PGE<sub>2</sub> Production by Arylsulfonamide Derivatives via the Selective Inhibition of mPGES-1 Enzyme
title_fullStr Inhibition of LPS-Induced PGE<sub>2</sub> Production by Arylsulfonamide Derivatives via the Selective Inhibition of mPGES-1 Enzyme
title_full_unstemmed Inhibition of LPS-Induced PGE<sub>2</sub> Production by Arylsulfonamide Derivatives via the Selective Inhibition of mPGES-1 Enzyme
title_sort inhibition of lps-induced pge<sub>2</sub> production by arylsulfonamide derivatives via the selective inhibition of mpges-1 enzyme
publisher MDPI AG
series Proceedings
issn 2504-3900
publishDate 2019-08-01
description Microsomal prostaglandin E synthase-1 (mPGES-1) is responsible for the massive prostaglandin E<sub>2</sub> (PGE<sub>2</sub>) formation during inflammation. Increasing evidence reveals mPGES-1 inhibitors as a safe alternative to nonsteroidal anti-inflammatory drugs. Recently, we reported that a novel series of phenylsulfonyl hydrazide derivatives could reduce LPS-induced PGE<sub>2</sub> levels in RAW 264.7 macrophage cells via an inhibition of the mPGES-1 enzyme. However, a few of the phenylsulfonyl hydrazide derivatives showed poor metabolic stability in liver microsomes. In order to identify new mPGES-1 inhibitors with improved metabolic stability, therefore, a series of arylsulfonamide derivatives has been synthesized and biologically evaluated against PGE<sub>2</sub> production and the mPGES-1 enzyme. Among them, MPO-0186 inhibits the production of PGE<sub>2</sub> (IC<sub>50</sub> = 0.20 &#956;M) in A549 cells via inhibition of mPGES-1 (IC<sub>50</sub> = 0.49 &#956;M in a cell-free assay) together with high selectivity over both COX-1 and COX-2. A molecular docking study theoretically suggests that MPO-0186 could inhibit PGE<sub>2</sub> production by blocking the PGH<sub>2</sub> binding site of the mPGES-1 enzyme. Furthermore, MPO-0186 demonstrated good metabolic stability in human liver microsomes and no significant inhibition observed in clinically relevant CYP isoforms.
topic mPGES-1
inflammation
arylsulfonamides
url https://www.mdpi.com/2504-3900/22/1/37
work_keys_str_mv AT misongkim inhibitionoflpsinducedpgesub2subproductionbyarylsulfonamidederivativesviatheselectiveinhibitionofmpges1enzyme
AT changyoungjang inhibitionoflpsinducedpgesub2subproductionbyarylsulfonamidederivativesviatheselectiveinhibitionofmpges1enzyme
AT yunchannam inhibitionoflpsinducedpgesub2subproductionbyarylsulfonamidederivativesviatheselectiveinhibitionofmpges1enzyme
AT kyungtaelee inhibitionoflpsinducedpgesub2subproductionbyarylsulfonamidederivativesviatheselectiveinhibitionofmpges1enzyme
AT jaeyeollee inhibitionoflpsinducedpgesub2subproductionbyarylsulfonamidederivativesviatheselectiveinhibitionofmpges1enzyme
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