4 research outputs found
The Hypolipidemic Natural Product Guggulsterone Is a Promiscuous Steroid Receptor Ligand
Discovery of 6‑(4-{[5-Cyclopropyl-3-(2,6-dichlorophenyl)Âisoxazol-4-yl]methoxy}Âpiperidin-1-yl)-1-methyl‑1<i>H</i>‑indole-3-carboxylic Acid: A Novel FXR Agonist for the Treatment of Dyslipidemia
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