Molecule

Description

Cancer

Description

WAY-362450 is a potent, selective FXR agonist with EC50 of 4 nM.

Targets

IC₅₀

In Vitro

WAY-362450 binds to the ligand-binding domain (LBD) of human FXR. WAY-362450 resides in a predominately hydrophobic pocket with only a few polar atoms making contact with WAY-362450. WAY-362450 promotes transcription of the human BSEP, human SHP, and mouse IBABP genes utilizing reporter constructs with EC50 of 17, 230, and 33 nM, respectively in promoter assays. WAY-362450 at concentration of 1 μM significantly induces mRNAs encoding for BSEP, SHP, and IBABP in human cell cultures to 13-, 2-, and 20-fold, respectively. ^[1] WAY-362450 at concentration of 1 μM suppresses interleukin-6-induced CRP expression in human Hep3B hepatoma cells, and the inhibitory effect is attenuated when knockdown of FXR by short interfering RNA.

In Vivo

WAY-362450 administrated intravenously or orally at does of 3 mg/kg in rats with a protracted half-life of 25 h, modest volume of distribution, and low clearance of 3.3 L/kg. WAY-362450 administered orally at dose of 10 mg/kg in normal C57bl/6 mice for a period of 7 days significantly lowers triglycerides to 62.0 ± 6.4 mg/dL and total cholesterol to 78.1 ± 5.0 mg/dL. WAY-362450 administered orally at dose of 1 and 3 mg/kg daily for 6 weeks in LDLR^?/? mice, triglycerides is lowered by 19% and 39%, respectively, total cholesterol is lowered by 23% and 50%, respectively and lesion formation by 18% and 36%, respectively. ^[1] WAY-362450 intraperitoneally administrated at dose of 30 mg/kg daily for 4 days in wild type C57BL/6 mice attenuates lipopolysaccharide-induced serum amyloid P component and serum amyloid A3 mRNA levels in the liver. ^[3] WAY-362450 orally administered at dose of 30 mg/kg/day for 4 weeks in adult male C57BL/6 mice reduces in?ammatory cell in?ltration and hepatic ?brosis, the reduction in in?ammatory cell in?ltration correlates with deceased serum levels of keratinocyte derived chemokine (mKC) and MCP 1 and decreased hepatic gene expression of MCP-1 and VCAM-1, and the reduction of hepatic ?brosis by WAY-362450 treatment corresponded to a reduction in hepatic gene expression of ?brosis markers. ^[3] WAY-362450 administrated orally at dose of 30mg/kg in LDLR^?/? and apoE^?/? mice blocks diet-induced hypertriglyceridemia and elevations of non-HDL cholesterol and produced a near complete inhibition of aortic lesion formation, WAY-362450 also induced small heterodimer partner (SHP) expression and repressed cholesterol 7α-hydroxylase (CYP7A1) and sterol 12 α-hydroxylase (CYP8B1) expression. ^[4]

Clinical Trials

WAY-362450 is currently on Phase I clinical trials, to examine safety, tolerability, and pharmacokinetics of WAY-362450 administered orally to healthy Japanese male subjects.

Features

Cross-reactivity Studies

The selectivity of 6m is evaluated using a panel of nuclear receptor expression plasmids in the forms of wild type receptors or chimeric receptors with Gal-DBD and NHR LBD transiently transfected to CV-1 cells in tissue culture flasks with the NHR responsive luciferase reporters. Except VDR assay, it is a two hybrid assay that measure the interaction of VP16 fused VDR-LBD and Gal-SRC1. The cells are harvested after 6 h transfection and seeded to the assay plates with diluted testing WAY-362450. Different than the agonist assay, the antagonist assay is carried out the in presence of an agonist at concentration of EC75. After 18 h of incubation, the media is removed from the plates and the lucifaerase activity is determined using the luciferase substrate. As shown in Tables S4-S5, compound 6m is highly selective, as little or no significant cross-reactivity with other nuclear hormone receptors is observed at concentrations up to 10 μM

Animal Models

Seven week old male C57bl/6 mice

Formulation

NMP:Solutol:PEG400:H2O, 10:10:40:40

Doses

10 mg/kg

Administration

Administrated orally once daily in the morning for a period of 7 days