1H-Imidazo[4,5-c]quinoline derivatives as novel potent TNF-alpha suppressors: synthesis and structure-activity relationship of 1-, 2-and 4-substituted 1H-imidazo[4,5-c]quinolines or 1H-imidazo[4,5-c]pyridines.
Structural modification of imiquimod (1), which is known as an interferon-alpha (IFN-alpha) inducer, for the aim of finding a novel and small-molecule tumor necrosis factor-alpha (TNF-alpha) suppressor and structure-activity relationship (SAR) are described. Structural modification of a imiquimod analogue, 4-amino-1-[2-(1-benzyl-4-piperidyl)ethyl-1H-imidazo[4,5-c]quinoline (2), which had moderate TNF-alpha suppressing activity without IFN-alpha inducing activity, led to a finding of 4-chloro-2-phenyl-1-[2-(4-piperidyl)ethyl]-1H-imidazo[4,5-c]quinoline (10) with potent TNF-alpha suppressing activity. The relation between conformational direction of 2-(4-piperidyl)ethyl group at position 1 and TNF-alpha suppressing activity is also demonstrated by NMR.
Izumi
Tomoyuki
T
Research Division, R&D Headquarters, Hokuriku Seiyaku Co., Ltd., 37-1-1, Inokuchi, Katsuyama, Fukui 911-8555, Japan. tomoyuki.izumi@abbott.com
Sakaguchi
Jun
J
Takeshita
Makoto
M
Tawara
Harumi
H
Kato
Ken-ichi
K
Dose
Hitomi
H
Tsujino
Tomomi
T
Watanabe
Yoshinari
Y
Kato
Hideo
H
D000328:Adult; D006801:Humans; D007093:Imidazoles / Q000737:chemistry / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D008968:Molecular Conformation; D011725:Pyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D011804:Quinolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors*
D007093:Imidazoles; D011725:Pyridines; D011804:Quinolines; D014409:Tumor Necrosis Factor-alpha