Discovery of N-(1-(3-(4-phenoxyphenyl)-1,2,4-oxadiazol-5-yl)ethyl)acetamides as novel acetyl-CoA carboxylase 2 (ACC2) inhibitors with peroxisome proliferator-activated receptor α/δ (PPARα/δ) dual agonistic activity

Shogo Okazaki, Tomomi Noguchi-Yachide, Taki Sakai, Minoru Ishikawa, Makoto Makishima, Yuichi Hashimoto, Takao Yamaguchi

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

Acetyl-CoA carboxylases (ACCs) catalyze a critical step in de novo lipogenesis, and are considered as promising targets for treatment of obesity, dyslipidemia and type 2 diabetes mellitus. On the other hand, peroxisome proliferator-activated receptors (PPARs) are well-established therapeutic targets for these metabolic syndrome-related diseases. Therefore, we considered that dual modulators of ACC and PPARs would be promising candidates as therapeutic agents. Here, we designed a series of acetamides based on the molecular similarity between ACC inhibitors and PPAR agonists. Screening of the synthesized compounds identified N-(1-(3-(4-phenoxyphenyl)-1,2,4-oxadiazol-5-yl)ethyl)acetamides as novel ACC2 inhibitors with PPARα/PPARδ dual agonistic activity. Structure–activity relationship studies and further structural elaboration afforded compounds with distinct activity profiles. Our findings should be helpful for the discovery of candidate agents with an appropriate balance of ACC-inhibitory and PPAR-activating activities for therapeutic lipid control.

Original languageEnglish
Pages (from-to)5258-5269
Number of pages12
JournalBioorganic and Medicinal Chemistry
Volume24
Issue number21
DOIs
Publication statusPublished - 2016 Jan 1
Externally publishedYes

Keywords

  • Acetyl-CoA carboxylase
  • Multi-target drug
  • Peroxisome proliferator-activated receptor

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

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