期刊
BIOORGANIC & MEDICINAL CHEMISTRY
卷 24, 期 21, 页码 5455-5461出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmc.2016.08.067
关键词
Peroxisome proliferator-activated receptor; PPAR; PPAR agonist; Non-carboxylic acid
资金
- Ministry of Education, Culture, Sports, Science and Technology in Japan (MEXT) [26810091, 16K17930]
- Japan Society for the Promotion of Science (JSPS)
- Platform for Drug Discovery, Informatics, and Structural Life Science
- Grants-in-Aid for Scientific Research [16K17930, 26810091, 15K08015] Funding Source: KAKEN
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 PPAR alpha/delta dual agonists having an acetamide structure. Here, we describe structure-activity relationship (SAR) studies of these novel acetamide-based PPAR alpha/delta 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 PPAR alpha/delta dual agonist among the compounds synthesized (PPARc EC50 =17 nM, PPAR delta EC50 = 23 nM). (C) 2016 Elsevier Ltd. All rights reserved.
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