Portal de Periódicos da CAPES

Discovery, synthesis and biological evaluation of isoquinolones as novel and highly selective JNK inhibitors (2)

2008; Elsevier BV; Volume: 16; Issue: 8 Linguagem: Inglês

10.1016/j.bmc.2008.02.028

1464-3391

Yasutomi Asano, Shuji Kitamura, Taiichi Ohra, Fumio Itoh, Masahiro Kajino, Tomoko Tamura, Manami Kaneko, Shota Ikeda, Hideki Igata, Tomohiro Kawamoto, Satoshi Sogabe, Shin-ichi Matsumoto, Toshimasa Tanaka, Masashi Yamaguchi, Hiroyuki Kimura, Shoji Fukumoto,

Bioactive Compounds and Antitumor Agents

3-Metoxycarbonyl isoquinolone derivative 1 has been identified as a potent JNK inhibitor and significantly inhibited cardiac hypertrophy in a rat pressure-overload model. Herein, a series of isoquinolones with an imidazolylmethyl or a pyrazolylmethyl group at the 2-position were designed based on X-ray crystallographic analysis of the complex between the isoquinolone compound and JNK3, as wells as the relationship between compound lipophilicity (log D) and activity in a cell-based assay. The compounds prepared showed potent JNK1 inhibitory activities in a cell-based assay. Among them the isoquinolone derivative possessing 5-[(cyclopropylamino)carbonyl]-1-methyl-1H-pyrazole (16e) exhibited significant anti-hypertrophic activity at doses of more than 1 mg/kg (po) in a pressure-overload model.