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 alpha/delta (PPAR alpha/delta) dual agonistic activity

作者：Okazaki Shogo; Noguchi Yachide Tomomi; Sakai Taki; Ishikawa Minoru; Makishima Makoto; Hashimoto Yuichi; Yamaguchi Takao^*

来源：Bioorganic & Medicinal Chemistry, 2016, 24(21): 5258-5269.

DOI：10.1016/j.bmc.2016.08.045

• Acetyl-CoA carboxylase
• Peroxisome proliferator-activated receptor
• Multi-target drug

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 PPAR alpha/PPAR delta 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.

• 出版日期2016-11-1