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

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.