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Molecules 2017, 22(10), 1729; doi:10.3390/molecules22101729

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

1
Department of Pharmaceutical and Medicinal Chemistry, Institute of Pharmaceutical Sciences, Eberhard Karls Universität Tübingen, Auf der Morgenstelle 8, 72076 Tübingen, Germany
2
Teva-ratiopharm, Graf-Arco-Str. 3, 89079 Ulm, Germany
*
Author to whom correspondence should be addressed.
Received: 13 September 2017 / Revised: 5 October 2017 / Accepted: 10 October 2017 / Published: 14 October 2017
(This article belongs to the Special Issue Kinase Inhibitors)
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Abstract

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. View Full-Text
Keywords: kinase inhibitors; p38α MAP kinase; trisubstituted imidazoles; metabolic stability; Alzheimer’s disease; neurodegenerative diseases; cancer kinase inhibitors; p38α MAP kinase; trisubstituted imidazoles; metabolic stability; Alzheimer’s disease; neurodegenerative diseases; cancer
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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MDPI and ACS Style

Heider, F.; Haun, U.; Döring, E.; Kudolo, M.; Sessler, C.; Albrecht, W.; Laufer, S.; Koch, P. From 2-Alkylsulfanylimidazoles to 2-Alkylimidazoles: An Approach towards Metabolically More Stable p38α MAP Kinase Inhibitors. Molecules 2017, 22, 1729.

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