Synthesis and evaluation of new pirfenidone derivatives as anti-fibrosis agents.

Two series of new pirfenidone derivatives, in which phenyl groups or benzyl groups are attached to the nitrogen atom of the pyridin-2(1 H )-one moiety were synthesized and evaluated as anti-fibrosis agents. Among them, compound 5d, with a ( S )-2-(dimethylamino) propanamido group in the R 2 position (series 1) exhibited 10 times the anti-fibrosis activity (IC 50 : 0.245 mM) of pirfenidone (IC 50 : 2.75 mM). Compound 9d (series 2) gave an IC 50 of 0.035 mM against the human fibroblast cell line HFL1. The mechanism of the optimal compound inhibiting fibrosis was also studied.