Discovery of quinazolines as a novel structural class of potent inhibitors of NF-kappa B activation.
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.
Tobe
Masanori
M
Pharmaceuticals and Biotechnology Laboratory, Japan Energy Corporation, Toda-shi, Saitama 335-8502, Japan.
Isobe
Yoshiaki
Y
Tomizawa
Hideyuki
H
Nagasaki
Takahiro
T
Takahashi
Hirotada
H
Fukazawa
Tominaga
T
Hayashi
Hideya
H
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000737:chemistry / Q000494:pharmacology; D002351:Carrageenan / Q000633:toxicity; D004487:Edema / Q000139:chemically induced / Q000188:drug therapy; D006614:Hindlimb; D006801:Humans; D020128:Inhibitory Concentration 50; D019169:Jurkat Cells; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D011799:Quinazolines / Q000737:chemistry* / Q000494:pharmacology*; D051381:Rats; D013154:Spleen / Q000166:cytology / Q000187:drug effects / Q000254:growth & development; D013329:Structure-Activity Relationship; D015533:Transcriptional Activation / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000096:biosynthesis
D000894:Anti-Inflammatory Agents, Non-Steroidal; D016328:NF-kappa B; D011799:Quinazolines; D014409:Tumor Necrosis Factor-alpha; D002351:Carrageenan