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

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

Research output: Contribution to journalArticlepeer-review

1 Citation (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)595-607
Number of pages13
JournalHeterocycles
Volume95
Issue number1
DOIs
Publication statusPublished - 2017
Externally publishedYes

ASJC Scopus subject areas

  • Analytical Chemistry
  • Pharmacology
  • Organic Chemistry

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