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
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ABSTRACT: 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 (logD) 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 1mg/kg (po) in a pressure-overload model.
Bioorganic & medicinal chemistry 05/2008; 16(8):4699-714. · 2.82 Impact Factor
