Structure–activity relationship studies of non-carboxylic acid peroxisome proliferator-activated receptor α/δ (PPARα/δ) dual agonists

Shogo Okazaki, Ryuta Shioi, Tomomi Noguchi-Yachide, Minoru Ishikawa, Makoto Makishima, Yuichi Hashimoto, Takao Yamaguchi

Research output: Contribution to journalArticlepeer-review

7 Citations (Scopus)

Abstract

The peroxisome proliferator-activated receptors (PPARs) are ligand-dependent transcription factors that contribute to the regulation of lipid, glucose and cholesterol homeostases. They are considered as therapeutic targets for metabolic diseases such as dyslipidemia and type 2 diabetes mellitus. Various PPAR agonists have been developed, but most of them contain a carboxylic acid (CA) or thiazolidinedione (TZD) moiety, which is essential for the activity. However, we recently discovered non-CA/non-TZD class PPARα/δ dual agonists having an acetamide structure. Here, we describe structure–activity relationship (SAR) studies of these novel acetamide-based PPARα/δ dual agonists. The SAR studies revealed that the acetamide functionality and adjacent methyl group contribute greatly to the agonistic activity. Compound (S)-10 was the most potent PPARα/δ dual agonist among the compounds synthesized (PPARα EC50 = 17 nM, PPARδ EC50 = 23 nM).

Original languageEnglish
Pages (from-to)5455-5461
Number of pages7
JournalBioorganic and Medicinal Chemistry
Volume24
Issue number21
DOIs
Publication statusPublished - 2016 Jan 1
Externally publishedYes

Keywords

  • Non-carboxylic acid
  • PPAR
  • PPAR agonist
  • 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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