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

Abstract

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.

Regulation of lipid metabolism by obeticholic acid in hyperlipidemic hamsters

“…OCA also reduced hepatic TG contents (Fig. 2B), which was consistent with the reported effects of other FXR agonists on lowering hepatic TG (23,30,31). The cholesterol contents of fecal samples collected on day 0 and day 13 of the control group were nearly identical, but cholesterol levels were significantly increased in fecal samples after 13 days of OCA treatment (Fig.…”

Molecular tuning of farnesoid X receptor partial agonism

“…Importantly, conversion to bile acids accounts for approximately one third of cholesterol elimination. Partial FXR activation, therefore, appears as a valuable strategy to avoid mechanism-based side effects of FXR targeting and recently, promising preclinical and phase 1 clinical data of a partial FXR agonist have been reported 10 . Partial agonists induce activation of the NR with reduced activation efficacy compared to agonists which translates to modest modulation of FXR-regulated gene expression 11 .…”

Mechanism of Hydrophobic Bile Acid-Induced Hepatocyte Injury and Drug Discovery

“…It can reduce TG and LDL levels, and increase HDL levels. However, the indicators for regulating bile acid have not been evaluated (Genin et al, 2015). As a synthetic FXR agonist, GS-9674 mainly activates the expression of FGF19 by activating FXR on intestinal epithelial cells.…”