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Discovery, synthesis and biological evaluation of isoquinolones as novel and highly selective JNK inhibitors (1)

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

10.1016/j.bmc.2008.02.027

1464-3391

Yasutomi Asano, Shuji Kitamura, Taiichi Ohra, Kazuyoshi Aso, Hideki Igata, Tomoko Tamura, Tomohiro Kawamoto, Toshimasa Tanaka, Satoshi Sogabe, Shin-ichi Matsumoto, Masashi Yamaguchi, Hiroyuki Kimura, Fumio Itoh,

Cytokine Signaling Pathways and Interactions

A novel series of 4-phenylisoquinolones were synthesized and evaluated as c-Jun N-terminal kinase (JNK) inhibitors. Initial modification at the 2- and 3-positions of the isoquinolone ring of hit compound 4, identified from high-throughput screening, led to the lead compound 6b. The optimization was carried out using a JNK1-binding model of 6b and several compounds exhibited potent JNK inhibition. Among them, 11g significantly inhibited cardiac hypertrophy in rat pressure-overload models without affecting blood pressure and the concept of JNK inhibitors as novel therapeutic agents for heart failure was confirmed.