Structural development studies of pyrazoloketone-derived acetyl-CoA carboxylase inhibitors

Shogo Okazaki, Taki Sakai, Minoru Ishikawa, Yuichi Hashimoto, Takao Yamaguchi

研究成果: Article査読

1 被引用数 (Scopus)

抄録

Acetyl-CoA carboxylase (ACC) plays a key role in fatty acid homeostasis in humans, and inhibitors of ACC are expected to inhibit fatty acid biosynthesis and to activate fatty acid β-oxidation. Therefore, they are considered to be candidates for treatment of metabolic syndrome and related diseases. In this context, an upstream kinase of ACC, adenosine monophosphate-activated protein kinase (AMPK), has also recently emerged as a potential therapeutic target, because it phosphorylates and inactivates ACC. Here, we designed a fused molecule consisting of a pyrazoloketone-type ACC inhibitor and a recently discovered AMPK activator, aiming to develop a novel combined ACC inhibitor/AMPK activator to regulate fatty acid levels. The designed compound was prepared through a convergent synthetic route. This compound and its methyl ester analogue showed potent ACC2-inhibitory activity with IC50 values of 8.8 and 1.3 μM, respectively. Exomethylene derivatives, obtained from an unexpected side reaction during deprotection, also exhibited ACC2-inhibitory activity.

本文言語English
ページ(範囲)595-607
ページ数13
ジャーナルHeterocycles
95
1
DOI
出版ステータスPublished - 2017
外部発表はい

ASJC Scopus subject areas

  • 分析化学
  • 薬理学
  • 有機化学

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