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

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 PPAR alpha/delta dual agonists having an acetamide structure. Here, we describe structure-activity relationship (SAR) studies of these novel acetamide-based PPAR alpha/delta 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 PPAR alpha/delta dual agonist among the compounds synthesized (PPARc EC50 =17 nM, PPAR delta EC50 = 23 nM). (C) 2016 Elsevier Ltd. All rights reserved.