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From 2-Alkylsulfanylimidazoles to 2-Alkylimidazoles: An Approach towards Metabolically More Stable p38α MAP Kinase Inhibitors

In vitro and in vivo metabolism studies revealed that 2-alkylsulfanylimidazole ML3403 (4-(5-(4-fluorophenyl)-2-(methylthio)-1H-imidazol-4-yl)-N-(1-phenylethyl)pyridin-2-amine) undergoes rapid oxidation to the sulfoxide. Replacing the sulfur atom present in the two potent p38α mitogen-activated prote...

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Autores principales: Heider, Fabian, Haun, Urs, Döring, Eva, Kudolo, Mark, Sessler, Catharina, Albrecht, Wolfgang, Laufer, Stefan, Koch, Pierre
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6151569/
https://www.ncbi.nlm.nih.gov/pubmed/29036906
http://dx.doi.org/10.3390/molecules22101729
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author Heider, Fabian
Haun, Urs
Döring, Eva
Kudolo, Mark
Sessler, Catharina
Albrecht, Wolfgang
Laufer, Stefan
Koch, Pierre
author_facet Heider, Fabian
Haun, Urs
Döring, Eva
Kudolo, Mark
Sessler, Catharina
Albrecht, Wolfgang
Laufer, Stefan
Koch, Pierre
author_sort Heider, Fabian
collection PubMed
description In vitro and in vivo metabolism studies revealed that 2-alkylsulfanylimidazole ML3403 (4-(5-(4-fluorophenyl)-2-(methylthio)-1H-imidazol-4-yl)-N-(1-phenylethyl)pyridin-2-amine) undergoes rapid oxidation to the sulfoxide. Replacing the sulfur atom present in the two potent p38α mitogen-activated protein (MAP) kinase inhibitors ML3403 and LN950 (2-((5-(4-fluorophenyl)-4-(2-((3-methylbutan-2-yl)amino)pyridin-4-yl)-1H-imidazol-2-yl)thio)ethan-1-ol) by a methylene group resulted in 2-alkylimidazole derivatives 1 and 2, respectively, having a remarkably improved metabolic stability. The 2-alkylimidazole analogs 1 and 2 showed 20% and 10% biotransformation after 4 h of incubation with human liver microsomes, respectively. They display a 4-fold increased binding affinity towards the target kinase as well as similar in vitro potency and ex vivo efficacy relative to their 2-alkylsulfanylimidazole counterparts ML3403 and LN950. For example, 2-alkylimidazole 2, the analog of LN950, inhibits both the p38α MAP kinase as well as the LPS-stimulated tumor necrosis factor-α release from human whole blood in the low double-digit nanomolar range.
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spelling pubmed-61515692018-11-13 From 2-Alkylsulfanylimidazoles to 2-Alkylimidazoles: An Approach towards Metabolically More Stable p38α MAP Kinase Inhibitors Heider, Fabian Haun, Urs Döring, Eva Kudolo, Mark Sessler, Catharina Albrecht, Wolfgang Laufer, Stefan Koch, Pierre Molecules Article In vitro and in vivo metabolism studies revealed that 2-alkylsulfanylimidazole ML3403 (4-(5-(4-fluorophenyl)-2-(methylthio)-1H-imidazol-4-yl)-N-(1-phenylethyl)pyridin-2-amine) undergoes rapid oxidation to the sulfoxide. Replacing the sulfur atom present in the two potent p38α mitogen-activated protein (MAP) kinase inhibitors ML3403 and LN950 (2-((5-(4-fluorophenyl)-4-(2-((3-methylbutan-2-yl)amino)pyridin-4-yl)-1H-imidazol-2-yl)thio)ethan-1-ol) by a methylene group resulted in 2-alkylimidazole derivatives 1 and 2, respectively, having a remarkably improved metabolic stability. The 2-alkylimidazole analogs 1 and 2 showed 20% and 10% biotransformation after 4 h of incubation with human liver microsomes, respectively. They display a 4-fold increased binding affinity towards the target kinase as well as similar in vitro potency and ex vivo efficacy relative to their 2-alkylsulfanylimidazole counterparts ML3403 and LN950. For example, 2-alkylimidazole 2, the analog of LN950, inhibits both the p38α MAP kinase as well as the LPS-stimulated tumor necrosis factor-α release from human whole blood in the low double-digit nanomolar range. MDPI 2017-10-14 /pmc/articles/PMC6151569/ /pubmed/29036906 http://dx.doi.org/10.3390/molecules22101729 Text en © 2017 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Heider, Fabian
Haun, Urs
Döring, Eva
Kudolo, Mark
Sessler, Catharina
Albrecht, Wolfgang
Laufer, Stefan
Koch, Pierre
From 2-Alkylsulfanylimidazoles to 2-Alkylimidazoles: An Approach towards Metabolically More Stable p38α MAP Kinase Inhibitors
title From 2-Alkylsulfanylimidazoles to 2-Alkylimidazoles: An Approach towards Metabolically More Stable p38α MAP Kinase Inhibitors
title_full From 2-Alkylsulfanylimidazoles to 2-Alkylimidazoles: An Approach towards Metabolically More Stable p38α MAP Kinase Inhibitors
title_fullStr From 2-Alkylsulfanylimidazoles to 2-Alkylimidazoles: An Approach towards Metabolically More Stable p38α MAP Kinase Inhibitors
title_full_unstemmed From 2-Alkylsulfanylimidazoles to 2-Alkylimidazoles: An Approach towards Metabolically More Stable p38α MAP Kinase Inhibitors
title_short From 2-Alkylsulfanylimidazoles to 2-Alkylimidazoles: An Approach towards Metabolically More Stable p38α MAP Kinase Inhibitors
title_sort from 2-alkylsulfanylimidazoles to 2-alkylimidazoles: an approach towards metabolically more stable p38α map kinase inhibitors
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6151569/
https://www.ncbi.nlm.nih.gov/pubmed/29036906
http://dx.doi.org/10.3390/molecules22101729
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