TY - JOUR
T1 - Structure–activity relationship studies of non-carboxylic acid peroxisome proliferator-activated receptor α/δ (PPARα/δ) dual agonists
AU - Okazaki, Shogo
AU - Shioi, Ryuta
AU - Noguchi-Yachide, Tomomi
AU - Ishikawa, Minoru
AU - Makishima, Makoto
AU - Hashimoto, Yuichi
AU - Yamaguchi, Takao
N1 - Funding Information:
The work described in this paper was partially supported by Grants-in-Aid for Scientific Research (KAKENHI, Grant-in-Aid for Young Scientists (B), No. 26810091 and 16K17930 to T.Y.) from The Ministry of Education, Culture, Sports, Science and Technology in Japan (MEXT), and the Japan Society for the Promotion of Science (JSPS), and Platform for Drug Discovery, Informatics, and Structural Life Science .
Publisher Copyright:
© 2016 Elsevier Ltd
PY - 2016
Y1 - 2016
N2 - 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).
AB - 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).
KW - Non-carboxylic acid
KW - PPAR
KW - PPAR agonist
KW - Peroxisome proliferator-activated receptor
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U2 - 10.1016/j.bmc.2016.08.067
DO - 10.1016/j.bmc.2016.08.067
M3 - Article
C2 - 27622746
AN - SCOPUS:84991490331
SN - 0968-0896
VL - 24
SP - 5455
EP - 5461
JO - Bioorganic and Medicinal Chemistry
JF - Bioorganic and Medicinal Chemistry
IS - 21
ER -
