Discovery of 6-(4-{[5-Cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl]methoxy}piperidin-1-yl)-1-methyl-1H-indole-3-carboxylic Acid: A Novel FXR Agonist for the Treatment of Dyslipidemia
详细信息 查看全文
- 作者：Michael J. Genin ; Ana B. Bueno ; Javier Agejas Francisco ; Peter R. Manninen ; Wayne P. Bocchinfuso ; Chahrzad Montrose-Rafizadeh ; Ellen A. Cannady ; Timothy M. Jones ; John R. Stille ; Eyas Raddad ; Charles Reidy ; Amy Cox ; M. Dodson Michael ; Laura F. Michael
- 刊名：Journal of Medicinal Chemistry
- 出版年：2015
- 出版时间：December 24, 2015
- 年：2015
- 卷：58
- 期：24
- 页码：9768-9772
- 全文大小：286K
- ISSN：1520-4804
文摘
The farnesoid X receptor (FXR) is a member of the “metabolic” subfamily of nuclear receptors. Several FXR agonists have been reported in the literature to have profound effects on plasma lipids in animal models. To discover novel and effective therapies for dyslipidemia and atherosclerosis, we have developed a series of potent FXR agonists that robustly lower plasma LDL and vLDL in LDLr–/– mice. To this end the novel piperidinylisoxazole system LY2562175 was discovered. This molecule is a potent and selective FXR agonist in vitro and has robust lipid modulating properties, lowering LDL and triglycerides while raising HDL in preclinical species. The preclinical ADME properties of LY2562175 were consistent with enabling once daily dosing in humans, and it was ultimately advanced to the clinic for evaluation in humans. The synthesis and biological profile of this molecule is discussed.