Abstract
We disclose here a new structural class of low-molecular-weight inhibitors of NF-kappa B activation that were designed and synthesized by starting from quinazoline derivative 6a. Structure-activity relationship (SAR) studies based on 6a elucidated the structural requirements essential for the inhibitory activity toward NF-kappa B transcriptional activation, and led to the identification of the 6-amino-4-phenethylaminoquinazoline skeleton as the basic framework. In this series of compounds, 11q, containing the 4-phenoxyphenethyl moiety at the C(4)-position, showed strong inhibitory effects on both NF-kappa B transcriptional activation and TNF-alpha production. Furthermore, 11q exhibited an anti-inflammatory effect on carrageenin-induced paw edema in rats.
MeSH terms
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Animals
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Anti-Inflammatory Agents, Non-Steroidal / chemistry
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Anti-Inflammatory Agents, Non-Steroidal / pharmacology
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Carrageenan / toxicity
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Edema / chemically induced
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Edema / drug therapy
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Hindlimb
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Humans
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Inhibitory Concentration 50
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Jurkat Cells
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Male
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Mice
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Mice, Inbred BALB C
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NF-kappa B / antagonists & inhibitors*
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NF-kappa B / metabolism*
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Quinazolines / chemistry*
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Quinazolines / pharmacology*
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Rats
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Spleen / cytology
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Spleen / drug effects
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Spleen / growth & development
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Structure-Activity Relationship
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Transcriptional Activation / drug effects
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Tumor Necrosis Factor-alpha / antagonists & inhibitors
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Tumor Necrosis Factor-alpha / biosynthesis
Substances
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Anti-Inflammatory Agents, Non-Steroidal
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NF-kappa B
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Quinazolines
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Tumor Necrosis Factor-alpha
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Carrageenan