Imidazole inhibitors of cytokine release: probing substituents in the 2 position

Stefan A Laufer; Hans-Günther Striegel; Gerd K Wagner

doi:10.1021/jm020873z

Imidazole inhibitors of cytokine release: probing substituents in the 2 position

J Med Chem. 2002 Oct 10;45(21):4695-705. doi: 10.1021/jm020873z.

Authors

Stefan A Laufer¹, Hans-Günther Striegel, Gerd K Wagner

Affiliation

¹ Institute of Pharmacy, Department of Pharmaceutical and Medicinal Chemistry, Eberhard-Karls-University Tübingen, Auf der Morgenstelle 8, 72076 Tübingen, Germany. stefan.laufer@uni-tuebingen.de

PMID: 12361396
DOI: 10.1021/jm020873z

Abstract

Novel 2,4,5-trisubstituted imidazole derivatives were prepared as potential anticytokine agents. Thirty-seven compounds were tested on their ability to inhibit the release of tumor necrosis factor-alpha (TNF-alpha) and interleukin-1beta (IL-1beta) from peripheral blood mononuclear cells (PBMC) or human whole blood. SARs (structure activity relationships) for substituents at the 4 and 5 position of the imidazole core were similar to those described for other inhibitors of cytokine release and p38 MAP (mitogen-activated protein) kinase. Starting from benzylsulfanyl imidazole 2b (IC(50) p38, 4.0 microM; TNF-alpha, 1.1 microM; IL-1beta, 0.38 microM), the contribution of substituents at the 2 position to enzyme inhibitory and cellular activity of test compounds was investigated. This strategy led to the identification of compound 2q (IC(50) p38, 0.63 microM; TNF-alpha, 0.90 microM; IL-1beta, 0.04 microM), which was 6-10 times more potent than the initial lead 2b with respect to inhibition of p38 and IL-1beta release and equipotently inhibited TNF-alpha release.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Anti-Inflammatory Agents, Non-Steroidal / chemical synthesis*
Anti-Inflammatory Agents, Non-Steroidal / chemistry
Anti-Inflammatory Agents, Non-Steroidal / pharmacology
Cytokines / antagonists & inhibitors*
Cytokines / biosynthesis
Cytokines / blood
Humans
Imidazoles / chemical synthesis*
Imidazoles / chemistry
Imidazoles / pharmacology
In Vitro Techniques
Interleukin-1 / antagonists & inhibitors
Interleukin-1 / biosynthesis
Interleukin-1 / blood
Mitogen-Activated Protein Kinases / antagonists & inhibitors
Mitogen-Activated Protein Kinases / chemistry
Pyridines / chemical synthesis*
Pyridines / chemistry
Pyridines / pharmacology
Structure-Activity Relationship
Tumor Necrosis Factor-alpha / antagonists & inhibitors
Tumor Necrosis Factor-alpha / biosynthesis
p38 Mitogen-Activated Protein Kinases

Substances

4-(5-(4-fluorophenyl)-2-methylsulfanyl-1H-imidazol-4-yl)pyridine
Anti-Inflammatory Agents, Non-Steroidal
Cytokines
Imidazoles
Interleukin-1
Pyridines
Tumor Necrosis Factor-alpha
Mitogen-Activated Protein Kinases
p38 Mitogen-Activated Protein Kinases