Imidazopyridine and Pyrazolopiperidine Derivatives as Novel Inhibitors of Serine Palmitoyl Transferase
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- 作者：Michael J. Genin ; Isabel C. Gonzalez Valcarcel ; William G. Holloway ; Jason Lamar ; Marian Mosior ; Eric Hawkins ; Thomas Estridge ; Jeffrey Weidner ; Thomas Seng ; David Yurek ; Lisa A. Adams ; Jennifer Weller ; Vincent L. Reynolds ; Joseph T. Brozinick
- 刊名：Journal of Medicinal Chemistry
- 出版年：2016
- 出版时间：June 23, 2016
- 年：2016
- 卷：59
- 期：12
- 页码：5904-5910
- 全文大小：446K
- 年卷期：0
- ISSN：1520-4804
文摘
To develop novel treatments for type 2 diabetes and dyslipidemia, we pursued inhibitors of serine palmitoyl transferase (SPT). To this end compounds 1 and 2 were developed as potent SPT inhibitors in vitro. 1 and 2 reduce plasma ceramides in rodents, have a slight trend toward enhanced insulin sensitization in DIO mice, and reduce triglycerides and raise HDL in cholesterol/cholic acid fed rats. Unfortunately these molecules cause a gastric enteropathy after chronic dosing in rats.