Tetrasubstituted Imidazole Inhibitors of Cytokine Release:  Probing Substituents in the N-1 Position

We prepared novel 1,2,4,5-tetrasubstituted imidazole derivatives with high anti-inflammatory activity by using our previously described regiospecific synthesis. Systematic optimization of the imidazole N-1 substituent resulted in compound 9b that potently inhibited the mitogen-activated protein kina...

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Veröffentlicht in:Journal of medicinal chemistry 2004-12, Vol.47 (25), p.6311-6325
Hauptverfasser: Laufer, Stefan A, Zimmermann, Werner, Ruff, Kathrin J
Format: Artikel
Sprache:eng
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Zusammenfassung:We prepared novel 1,2,4,5-tetrasubstituted imidazole derivatives with high anti-inflammatory activity by using our previously described regiospecific synthesis. Systematic optimization of the imidazole N-1 substituent resulted in compound 9b that potently inhibited the mitogen-activated protein kinase p38 (p38 IC50 = 0.218 μM) as well as the release of the proinflammatory cytokines interleukin-1β (ΙL-1β) and tumor necrosis factor α (TNFα) from human whole blood after stimulation with LPS. Furthermore, compound 9b exhibited reduced cytochrome P450 interaction in comparison with SB203580. This result is particularly important, since cytochrome P450 interaction is observed for some p38 inhibitors and in turn can potentially cause drug−drug interaction or lead to other hepatic changes such as P450 enzyme induction.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm0496584