TY - JOUR
T1 - 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
AU - Okazaki, Shogo
AU - Noguchi-Yachide, Tomomi
AU - Sakai, Taki
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 - 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.
AB - 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.
KW - Acetyl-CoA carboxylase
KW - Multi-target drug
KW - Peroxisome proliferator-activated receptor
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U2 - 10.1016/j.bmc.2016.08.045
DO - 10.1016/j.bmc.2016.08.045
M3 - Article
C2 - 27591006
AN - SCOPUS:84991451254
VL - 24
SP - 5258
EP - 5269
JO - Bioorganic and Medicinal Chemistry
JF - Bioorganic and Medicinal Chemistry
SN - 0968-0896
IS - 21
ER -