1. Academic Validation
  2. 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

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

  • Bioorg Med Chem. 2016 Nov 1;24(21):5258-5269. doi: 10.1016/j.bmc.2016.08.045.
Shogo Okazaki 1 Tomomi Noguchi-Yachide 1 Taki Sakai 1 Minoru Ishikawa 1 Makoto Makishima 2 Yuichi Hashimoto 1 Takao Yamaguchi 1
Affiliations

Affiliations

  • 1 Institute of Molecular and Cellular Biosciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan.
  • 2 Nihon University School of Medicine, 30-1 Oyaguchi-kamicho, Itabashi-ku, Tokyo 173-8610, Japan.
Abstract

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.

Keywords

Acetyl-CoA carboxylase; Multi-target drug; Peroxisome proliferator-activated receptor.

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