1. Academic Validation
  2. Switching subtype-selectivity: Fragment replacement strategy affords novel class of peroxisome proliferator-activated receptor α/δ (PPARα/δ) dual agonists

Switching subtype-selectivity: Fragment replacement strategy affords novel class of peroxisome proliferator-activated receptor α/δ (PPARα/δ) dual agonists

  • Bioorg Med Chem Lett. 2017 Jul 15;27(14):3131-3134. doi: 10.1016/j.bmcl.2017.05.037.
Ryuta Shioi 1 Shogo Okazaki 1 Tomomi Noguchi-Yachide 1 Minoru Ishikawa 1 Makoto Makishima 2 Yuichi Hashimoto 1 Takao Yamaguchi 3
Affiliations

Affiliations

  • 1 Institute of Molecular and Cellular Biosciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan.
  • 2 School of Medicine, Nihon University, 30-1 Oyaguchi-kamicho, Itabashi-ku, Tokyo 173-8610, Japan.
  • 3 Institute of Molecular and Cellular Biosciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan. Electronic address: yamaguchi@iam.u-tokyo.ac.jp.
Abstract

Peroxisome proliferator-activated receptors (PPARs) are important drug targets for treatment of dyslipidemia, type 2 diabetes, Cardiovascular Disease, nonalcoholic fatty liver disease and nonalcoholic steatohepatitis, and great efforts have been made to develop novel PPAR ligands. However, most existing PPAR ligands contain a carboxylic acid (CA) or thiazolidinedione (TZD) structure (acidic head group) that is essential for activity. We recently discovered non-CA/TZD class PPARα/δ partial agonists, which contain an acetamide moiety and adjacent methyl group, linked to a 1,2,4-oxadiazole ring ("fragment a"). We hypothesized that the acetamide structure might interact with the CA/TZD-binding pocket. To test this idea, we firstly replaced fragment a in one of our compounds with the α-alkoxy-CA structure often found in PPAR agonists. Secondly, we replaced the α-alkoxy-CA head group of several reported PPAR agonists with our acetamide-based fragment a. The agonistic activities of the synthesized hybrid compounds toward PPARs (PPARα, PPARγ and PPARδ) were evaluated by means of cell-based reporter gene assays. All the hybrid molecules showed PPAR-agonistic activities, but replacement of the α-alkoxy-CA head group altered the maximum efficacy and the subtype-specificity. The acetamide-based hybrid molecules showed partial agonism toward PPARα and PPARδ, whereas the α-alkoxy-CA-based molecules were generally selective for PPARα and PPARγ, with relatively high activation efficacies. Thus, the fragment replacement strategy appears promising for the development of novel acetamide-based PPARα/δ dual agonists.

Keywords

Hybrid molecule; Non-carboxylic acid; Non-thiazolidinedione; PPAR agonist; Peroxisome proliferator-activated receptor.

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