Structure-activity relationship studies of non-carboxylic acid peroxisome proliferator-activated receptor α/δ (PPARα/δ) dual agonists

Bioorg Med Chem. 2016 Nov 1;24(21):5455-5461. doi: 10.1016/j.bmc.2016.08.067.

Shogo Okazaki ¹, Ryuta Shioi ¹, Tomomi Noguchi-Yachide ¹, Minoru Ishikawa ¹, Makoto Makishima ², Yuichi Hashimoto ¹, Takao Yamaguchi ³

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.
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.

PMID: 27622746 DOI: 10.1016/j.bmc.2016.08.067

Abstract

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=17nM, PPARδ EC₅₀=23nM).

Keywords

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

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