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

Fabian Heider,Pierre Koch,Wolfgang Albrecht,Catharina Sessler,Mark Kudolo,Stefan Laufer,Eva Döring,Urs Haun

doi:10.3390/molecules22101729

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.

Highlights

The p38α mitogen-activated protein (MAP) kinase is a ubiquitously expressed serine/threonine kinase, which is implicated in various cellular processes such as cell survival, proliferation and differentiation
Because it promotes the expression of pro-inflammatory cytokines such as tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β), the p38α MAP kinase has received a lot of attention as a target for drug discovery programs since the mid-1990s
Ethanone was oxidized to the corresponding α-diketone in a

Summary

Introduction

The p38α mitogen-activated protein (MAP) kinase is a ubiquitously expressed serine/threonine kinase, which is implicated in various cellular processes such as cell survival, proliferation and differentiation Because it promotes the expression of pro-inflammatory cytokines such as tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β), the p38α MAP kinase has received a lot of attention as a target for drug discovery programs since the mid-1990s. Several p38α MAP kinase inhibitors were tested in clinical trials against cancer and chronic inflammatory diseases like rheumatoid arthritis or chronic obstructive pulmonary disease Despite these major efforts, up to date there is still no p38α MAP kinase inhibitor on the market, as most of the trials were terminated due to adverse events or lack of efficacy. Two phase II studies of selective p38α MAP kinase inhibitor VX-745 (Figure S1, supplementary materials) to treat Alzheimer’s disease have been completed [4,5]

Methods

Discussion

Conclusion