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

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.

Structural Optimization of a Pyridinylimidazole Scaffold: Shifting the Selectivity from p38α Mitogen-Activated Protein Kinase to c-Jun N-Terminal Kinase 3

“…One of the most serious limitations of previously reported 2-alkylsulfanylimidazoles is their severe metabolization consisting of oxidation of the thioether function to the corresponding sulfoxide. 48 Nevertheless, in vitro assays performed on compound 44 demonstrated a substantial metabolic stability, as approximately 80% of the unmodified compound was still present after 4 h incubation (Figure S6, Supporting Information ). The major metabolite formed still appears to be represented by the sulfoxide derivative (8.49%), although modifications at the 4-morpholinoaniline substituent might also be present.…”

“…Finally, additional tests were performed to assess the metabolic stability of methyl-substituted pyridinylimidazole 44 upon incubation with human liver microsomes. One of the most serious limitations of previously reported 2-alkylsulfanylimidazoles is their severe metabolization consisting of oxidation of the thioether function to the corresponding sulfoxide . Nevertheless, in vitro assays performed on compound 44 demonstrated a substantial metabolic stability, as approximately 80% of the unmodified compound was still present after 4 h incubation (Figure S6, Supporting Information).…”

2‐Alkylsulfanyl‐4(5)‐aryl‐5(4)‐heteroarylimidazoles: An Overview on Synthetic Strategies and Biological Activity

“…The most prominent example is represented by ML3403, which inhibits the target kinase in the double‐digit nanomolar range and the release of TNF‐α from human whole blood (HWB) in the low‐micromolar range. ML3403 served both as lead compound for further optimization studies and as reference compound in in vitro and in vivo studies . The pharmacokinetic profile of ML3403 was extensively investigated by Kammerer et al .…”

“…The pharmacokinetic profile of ML3403 was extensively investigated by Kammerer et al . In vitro (animal and human liver microsomes) as well as in vivo (Wistar rats) studies revealed the oxidation of the 2‐methylsulfanyl moiety at the imidazole‐C2 position into a 2‐methylsulfinyl being the predominant biotransformation reaction . Cytochrome P450 (CYP450)‐3A4 was identified to be the key isoform for this sulfoxidation reaction.…”

Special Issue: Kinase inhibitors

“…The metabolic stability of two potent pyridinylimidazole-based p38α mitogen-activated protein (MAP) kinase inhibitors ML3403 and LN950 was improved by Heider et al [ 7 ]. The novel metabolically stable inhibitors were extensively evaluated in various assays and compared to their parent compounds.…”