| Autor: |
Genin MJ, Bueno AB, Agejas Francisco J, Manninen PR, Bocchinfuso WP, Montrose-Rafizadeh C, Cannady EA, Jones TM, Stille JR; Chorus, Eli Lilly and Company , Lilly Corporate Center, Indianapolis, Indiana 46285, United States., Raddad E; Chorus, Eli Lilly and Company , Lilly Corporate Center, Indianapolis, Indiana 46285, United States., Reidy C, Cox A, Michael MD, Michael LF |
| Jazyk: |
angličtina |
| Zdroj: |
Journal of medicinal chemistry [J Med Chem] 2015 Dec 24; Vol. 58 (24), pp. 9768-72. Date of Electronic Publication: 2015 Dec 02. |
| DOI: |
10.1021/acs.jmedchem.5b01161 |
| Abstrakt: |
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. |
| Databáze: |
MEDLINE |
| Externí odkaz: |
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