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

被引:53
作者
Genin, Michael J. [1 ]
Bueno, Ana B. [1 ]
Francisco, Javier Agejas [1 ]
Manninen, Peter R. [1 ]
Bocchinfuso, Wayne P. [1 ]
Montrose-Rafizadeh, Chahrzad [1 ]
Cannady, Ellen A. [2 ]
Jones, Timothy M. [2 ]
Stille, John R. [5 ]
Raddad, Eyas [5 ]
Reidy, Charles [4 ]
Cox, Amy [3 ]
Michael, M. Dodson [3 ]
Michael, Laura F. [4 ]
机构
[1] Lilly Corp Ctr, Lilly Res Labs, Discovery Chem Res & Technol, Indianapolis, IN 46285 USA
[2] Lilly Corp Ctr, Lilly Res Labs, Drug Disposit & Metab, Indianapolis, IN 46285 USA
[3] Lilly Corp Ctr, Lilly Res Labs, Diabet Therapeut Area, Indianapolis, IN 46285 USA
[4] Lilly Corp Ctr, Lilly Res Labs, Cardiovasc & Metab Dis Therapeut Area, Indianapolis, IN 46285 USA
[5] Eli Lilly & Co, Lilly Corp Ctr, Chorus, Indianapolis, IN 46285 USA
关键词
FARNESOID-X-RECEPTOR; NUCLEAR RECEPTOR; BILE-ACIDS; LIGANDS;
D O I
10.1021/acs.jmedchem.5b01161
中图分类号
R914 [药物化学];
学科分类号
100705 [微生物与生化药学];
摘要
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.
引用
收藏
页码:9768 / 9772
页数:5
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