1. Structure–activity relationship studies of non-carboxylic acid peroxisome proliferator-activated receptor α/δ (PPARα/δ) dual agonists.
- Author
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Okazaki, Shogo, Shioi, Ryuta, Noguchi-Yachide, Tomomi, Ishikawa, Minoru, Makishima, Makoto, Hashimoto, Yuichi, and Yamaguchi, Takao
- Subjects
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PEROXISOME proliferator-activated receptors , *TRANSCRIPTION factors , *HOMEOSTASIS , *METABOLIC disorder treatment , *ACETAMIDE , *STRUCTURE-activity relationship in pharmacology - 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 EC 50 = 17 nM, PPARδ EC 50 = 23 nM). [ABSTRACT FROM AUTHOR]
- Published
- 2016
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