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

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.

journal_name

Bioorg Med Chem

journal_title

Bioorganic & medicinal chemistry

authors

Asano Y,Kitamura S,Ohra T,Itoh F,Kajino M,Tamura T,Kaneko M,Ikeda S,Igata H,Kawamoto T,Sogabe S,Matsumoto S,Tanaka T,Yamaguchi M,Kimura H,Fukumoto S

doi

10.1016/j.bmc.2008.02.028

subject

Has Abstract

pub_date

2008-04-15 00:00:00

pages

4699-714

issue

8

eissn

0968-0896

issn

1464-3391

pii

S0968-0896(08)00138-7

journal_volume

16

pub_type

杂志文章

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