propan-2-yl 3-(3,4-difluorobenzoyl)-1,1-dimethyl-1H,2H,3H,6H-azepino[4,5-b]indole-5-carboxylate

• ChemBase ID: 73185
• Molecular Formular: C25H24F2N2O3
• Molecular Mass: 438.4664664
• Monoisotopic Mass: 438.17549908
• SMILES: c1ccc2c(c1)c1c([nH]2)C(=CN(CC1(C)C)C(=O)c1ccc(c(c1)F)F)C(=O)OC(C)C
• Canonical SMILES: CC(OC(=O)C1=CN(CC(c2c1[nH]c1c2cccc1)(C)C)C(=O)c1ccc(c(c1)F)F)C
• InChI: InChI=1S/C25H24F2N2O3/c1-14(2)32-24(31)17-12-29(23(30)15-9-10-18(26)19(27)11-15)13-25(3,4)21-16-7-5-6-8-20(16)28-22(17)21/h5-12,14,28H,13H2,1-4H3
• InChIKey: INASOKQDNHHMRE-UHFFFAOYSA-N

NAMES AND DATABASE IDS

Names

• IUPAC name: propan-2-yl 3-(3,4-difluorobenzoyl)-1,1-dimethyl-1H,2H,3H,6H-azepino[4,5-b]indole-5-carboxylate
• IUPAC Traditional name: isopropyl 3-(3,4-difluorobenzoyl)-1,1-dimethyl-2H,6H-azepino[4,5-b]indole-5-carboxylate
• Synonyms: WAY-362450

Database IDs

• CAS Number: 629664-81-9
• PubChem SID: 162038105
• PubChem CID: 10026128

CALCULATED PROPERTIES

• Acid pKa: 13.579931
• H Acceptors: 2
• H Donor: 1
• LogD (pH = 5.5): 5.1097784
• LogD (pH = 7.4): 5.109778
• Log P: 5.1097784
• Molar Refractivity: 117.9023 cm^3
• Polarizability: 45.54642 Å^3
• Polar Surface Area: 62.4 Å^2
• Rotatable Bonds: 4
• Lipinski's Rule of Five: false

PROPERTIES

Safety Information

• Storage Condition: -20°C

Product Information

• Salt Data: Free Base

DETAILS

Selleck Chemicals - S2694

Research Area

• Description: Cancer

Biological Activity

• Description: WAY-362450 is a potent, selective FXR agonist with EC50 of 4 nM.
• Targets: FXR
• IC50: 4 nM ^[1]
• 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.

Protocol

• Protocol: Kinase Assay ^[1]
• 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
• Protocol: Animal Study ^[2]
• 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

References

• References: [1] Flatt B, et al. J Med Chem, 2009, 52(4), 904-907.
• References: [2] Zhang S, et al. J Hepatol, 2009, 51(2), 380-388.
• References: [3] Zhang S, et al. Biochem Biophys Res Commun, 2009, 379(2), 476-479.
• References: [4] Hartman HB, et al. J Lipid Res, 2009, 50(6), 1090-1100.

REFERENCES

• Flatt B, et al. J Med Chem, 2009, 52(4), 904-907.
• Zhang S, et al. J Hepatol, 2009, 51(2), 380-388.
• Zhang S, et al. Biochem Biophys Res Commun, 2009, 379(2), 476-479.
• Hartman HB, et al. J Lipid Res, 2009, 50(6), 1090-1100.