1H-Imidazo[4,5-c]quinoline derivatives as novel potent TNF-α 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

Abstract Structural modification of imiquimod ( 1 ), which is known as an interferon-α (IFN-α) inducer, for the aim of finding a novel and small-molecule tumor necrosis factor-α (TNF-α) suppressor and structure–activity relationship (SAR) are described. Structural modification of a imiquimod analogue, 4-amino-1-[2-(1-benzyl-4-piperidyl)ethyl-1 H -imidazo[4,5- c ]quinoline ( 2 ), which had moderate TNF-α suppressing activity without IFN-α inducing activity, led to a finding of 4-chloro-2-phenyl-1-[2-(4-piperidyl)ethyl]-1 H -imidazo[4,5 -c ]quinoline ( 10 ) with potent TNF-α suppressing activity. The relation between conformational direction of 2-(4-piperidyl)ethyl group at position 1 and TNF-α suppressing activity is also demonstrated by NMR.