Design, synthesis, and structure–activity relationships of piperidine and dehydropiperidine carboxylic acids as novel, potent dual PPARα/γ agonists

• Published in: Bioorganic & medicinal chemistry 2008-06, Vol.18 (12), p.3545-3550
• Main Authors: Ye, Xiang-Yang, Li, Yi-Xin, Farrelly, Dennis, Flynn, Neil, Gu, Liqun, Locke, Kenneth T., Lippy, Jonathan, O’Malley, Kevin, Twamley, Celeste, Zhang, Litao, Ryono, Denis E., Zahler, Robert, Hariharan, Narayanan, Cheng, Peter T.W.
• Format: Article
• Language: English
• Subjects: Biological and medical sciences; Dual agonists; General and cellular metabolism. Vitamins; Medical sciences; Peroxisome proliferator-activated receptors; Pharmacology. Drug treatments; Piperidine and dehydropiperidine carboxylic acids; Structure–activity relationships
• ISSN: 0960-894X; 0968-0896; 1464-3405; 1464-3391
• DOI: 10.1016/j.bmcl.2008.05.014

The SAR of substituted dehydropiperidine and piperidine-4-carboxylic acid analogs as novel, potent dual PPARα/γ agonists is discussed. A rare double bond migration in dehydropiperidine series has been observed and discussed. Several series of substituted dehydropiperidine and piperidine-4-carboxylic acid analogs have been designed and synthesized as novel, potent dual PPARα/γ agonists. The SAR of these series of analogs is discussed. A rare double bond migration occurred during the basic hydrolysis of the α,β-unsaturated dehydropiperidine esters 12, and the structures of the migration products were confirmed through a series of 2D NMR experiments.