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.
D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D016207:Cytokines / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000097:blood; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D066298:In Vitro Techniques; D007375:Interleukin-1 / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000097:blood; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000737:chemistry; D011725:Pyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D048051:p38 Mitogen-Activated Protein Kinases
C467225:4-(5-(4-fluorophenyl)-2-methylsulfanyl-1H-imidazol-4-yl)pyridine; D000894:Anti-Inflammatory Agents, Non-Steroidal; D016207:Cytokines; D007093:Imidazoles; D007375:Interleukin-1; D011725:Pyridines; D014409:Tumor Necrosis Factor-alpha; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases