Discovery, synthesis and biological evaluation of isoquinolones as novel and highly selective JNK inhibitors (2) |
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Authors: | Asano Yasutomi Kitamura Shuji Ohra Taiichi Itoh Fumio Kajino Masahiro Tamura Tomoko Kaneko Manami Ikeda Shota Igata Hideki Kawamoto Tomohiro Sogabe Satoshi Matsumoto Shin-ichi Tanaka Toshimasa Yamaguchi Masashi Kimura Hiroyuki Fukumoto Shoji |
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Affiliation: | Medicinal Chemistry Research Laboratories, Pharmaceutical Research Division, Takeda Pharmaceutical Company, Ltd, 17-85, Jusohonmachi 2-chome, Osaka 532-8686, Japan. Asano_Yasutimi@takeda.co.jp |
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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. |
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