Nuclear factor-kappaB mediated inhibition of cytokine production by imidazoline scaffolds

• Published in: Journal of medicinal chemistry Vol. 52; no. 5; pp. 1302 - 1309
• Main Authors: Kahlon, Daljinder K, Lansdell, Theresa A, Fisk, Jason S, Hupp, Christopher D, Friebe, Timothy L, Hovde, Stacy, Jones, A Daniel, Dyer, Richard D, Henry, R William, Tepe, Jetze J
• Format: Journal Article
• Language: English
• Published: United States 12.03.2009
• Subjects: Anti-Inflammatory Agents, Non-Steroidal - chemical synthesis; Anti-Inflammatory Agents, Non-Steroidal - chemistry; Anti-Inflammatory Agents, Non-Steroidal - pharmacology; HeLa Cells; Humans; Imidazolines - chemical synthesis; Imidazolines - chemistry; Imidazolines - pharmacology; In Vitro Techniques; Interleukin-1beta - pharmacology; Interleukin-6 - antagonists & inhibitors; Interleukin-6 - biosynthesis; NF-kappa B - genetics; NF-kappa B - physiology; Stereoisomerism; Structure-Activity Relationship; Transcription, Genetic - drug effects; Tumor Necrosis Factor-alpha - antagonists & inhibitors; Tumor Necrosis Factor-alpha - biosynthesis
• ISSN: 1520-4804
• DOI: 10.1021/jm8013162

The mammalian nuclear transcription factor NF-kappaB is responsible for the transcription of multiple cytokines, including the pro-inflammatory cytokines tumor necrosis factor alpha (TNF-alpha) and interleukin 6 (IL-6). Elevated levels of pro-inflammatory cytokines play an important role in the pathogenesis of inflammatory disorders such as rheumatoid arthritis (RA). Inhibition of the pro-inflammatory transcription factor NF-kappaB has therefore been identified as a possible therapeutic treatment for RA. We describe herein the synthesis and biological activity of a series of imidazoline-based scaffolds as potent inhibitors of NF-kappaB mediated gene transcription in cell culture as well as inhibitors of TNF-alpha and IL-6 production in interleukin 1 beta (IL-1beta) stimulated human blood.