Discovery of quinazolines as a novel structural class of potent inhibitors of NF-kappa B activation

Bioorg Med Chem. 2003 Feb 6;11(3):383-91. doi: 10.1016/s0968-0896(02)00440-6.

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

  • Animals
  • Anti-Inflammatory Agents, Non-Steroidal / chemistry
  • Anti-Inflammatory Agents, Non-Steroidal / pharmacology
  • Carrageenan / toxicity
  • Edema / chemically induced
  • Edema / drug therapy
  • Hindlimb
  • Humans
  • Inhibitory Concentration 50
  • Jurkat Cells
  • Male
  • Mice
  • Mice, Inbred BALB C
  • NF-kappa B / antagonists & inhibitors*
  • NF-kappa B / metabolism*
  • Quinazolines / chemistry*
  • Quinazolines / pharmacology*
  • Rats
  • Spleen / cytology
  • Spleen / drug effects
  • Spleen / growth & development
  • Structure-Activity Relationship
  • Transcriptional Activation / drug effects
  • Tumor Necrosis Factor-alpha / antagonists & inhibitors
  • Tumor Necrosis Factor-alpha / biosynthesis

Substances

  • Anti-Inflammatory Agents, Non-Steroidal
  • NF-kappa B
  • Quinazolines
  • Tumor Necrosis Factor-alpha
  • Carrageenan