| Size | Price | Stock | Qty |
|---|---|---|---|
| 1mg |
|
||
| 5mg |
|
||
| Other Sizes |
| Targets |
EC50: 1.37 nM (FXR, TR-FRET), 1.55 nM (FXR, luciferase reporter assay)[1].
Farnesoid X receptor (FXR). |
|---|---|
| ln Vitro |
HEC96719 activates FXR with EC50 values of 1.37 nM (time-resolved fluorescence energy transfer (TR-FRET) assay) and 1.55 nM (luciferase reporter assay). It induces the expression of FXR target genes including fibroblast growth factor 15 (FGF15) and bile salt export pump (BSEP). It exhibits excellent potency superior to the first-generation FXR agonists GW4064 and obeticholic acid.
|
| ln Vivo |
It has been demonstrated that HEC96719 (0.5, 1.5, and 5 mg/kg; orally, once daily for 14 days) activates FXR via raising levels of fibroblast growth factor 15 (FGF15)[1]. FGF15 levels in the ileum and hepatic bile salt export pump (BSEP) levels are elevated by HEC96719 (5 mg/kg; oral, 1 dosage)[1]. In non-alcoholic steatohepatitis (NASH), HEC96719 (0.1, 0.3, and 1 mg/kg; orally, once day for 6 weeks) dramatically reduces symptoms[1]. HEC96719 (0.1, 0.3, and 1 mg/kg; taken orally once daily for four weeks) is better than obeticholic acid (OCA) in terms of improving liver fibrosis[1].
|
| Enzyme Assay |
The FXR agonist activity is determined using a TR-FRET coactivator assay. His-tagged FXR-LBD protein is incubated with HEC96719, a biotinylated SRC-1 coactivator peptide, and a terbium-labeled anti-His antibody. After equilibration, TR-FRET signals are measured, and EC50 is calculated. Additionally, a cell-based luciferase reporter assay is used where HEK293 cells are transfected with a GAL4-FXR-LBD construct and a luciferase reporter.
|
| Cell Assay |
The cell-based FXR activation assay is performed using an FXR-responsive reporter cell line (e.g., Huh7 cells co-transfected with an FXR expression vector and an FXR response element-luciferase reporter). Cells are treated with HEC96719 for 16-24 hours. Luciferase activity is measured and normalized to cell viability. EC50 values are calculated. Alternatively, endogenous FXR target gene expression is measured by qRT-PCR.
|
| Animal Protocol |
Animal/Disease Models: Male ob/ob nonalcoholic steatohepatitis (NASH) mouse models[1]
Doses: 0.1, 0.3 and 1 mg/kg Route of Administration: Oral administration; 0.1, 0.3 and 1 mg/kg, one time/day for 6 weeks Experimental Results: diminished levels of serum alanine aminotransferase (ALT) and liver triglyceride (TG), dose-dependently increased NASH activity and decreased NASH activity score. Animal/Disease Models: Male C57BL/6 liver fibrosis mouse models[1] Doses: 0.1, 0.3 and 1 mg/kg Route of Administration: Oral administration; 0.1, 0.3 and 1 mg/kg, one time/day for 4 weeks Experimental Results: diminished levels of serum ALT and TBIL, and decreased fibrosis area. In vivo studies are conducted in mouse models of NASH (e.g., high-fat diet-fed mice or STAM™ model). HEC96719 is administered orally once daily at doses of 0.5, 1.5, and 5 mg/kg for 14 days. FXR activation is confirmed by measuring increased levels of serum FGF15 and hepatic BSEP expression. It significantly improves NASH and liver fibrosis with good tissue distribution in the liver and intestines. |
| ADME/Pharmacokinetics |
HEC96719 is orally active and exhibits good tissue distribution, particularly in the liver and intestines, which are key sites of FXR expression. Detailed PK parameters (Cmax, Tmax, half-life, oral bioavailability) are not publicly disclosed but have been characterized as part of its preclinical profile for NASH. It is likely metabolized by CYP3A4.
|
| Toxicity/Toxicokinetics |
No detailed toxicology data are publicly available for HEC96719. However, as a potent FXR agonist, potential liabilities include pruritus (itching) and dyslipidemia (increased LDL cholesterol), which are class effects of FXR agonists. Standard preclinical safety studies in two species would be required for drug development.
|
| References | |
| Additional Infomation |
HEC96719 is an investigational drug candidate for nonalcoholic steatohepatitis (NASH) and liver fibrosis but is not yet approved for clinical use. It is a tricyclic FXR agonist that has shown excellent in vitro and in vivo potency, superior to older FXR agonists. It represents a next-generation FXR agonist with a novel chemical scaffold and favorable liver distribution.
|
| Molecular Formula |
C29H22CL2N2O5
|
|---|---|
| Molecular Weight |
549.401385784149
|
| Exact Mass |
548.09
|
| CAS # |
2181834-03-5
|
| PubChem CID |
138675487
|
| Appearance |
White to off-white solid powder
|
| LogP |
6.3
|
| Hydrogen Bond Donor Count |
1
|
| Hydrogen Bond Acceptor Count |
7
|
| Rotatable Bond Count |
6
|
| Heavy Atom Count |
38
|
| Complexity |
877
|
| Defined Atom Stereocenter Count |
0
|
| SMILES |
C1CC1C2=C(C(=NO2)C3=C(C=CC=C3Cl)Cl)COC4=NC5=C(C=C4)OC6=C(CC57CC7)C=CC(=C6)C(=O)O
|
| InChi Key |
JZJOXLSYULKNLW-UHFFFAOYSA-N
|
| InChi Code |
InChI=1S/C29H22Cl2N2O5/c30-19-2-1-3-20(31)24(19)25-18(26(38-33-25)15-4-5-15)14-36-23-9-8-21-27(32-23)29(10-11-29)13-17-7-6-16(28(34)35)12-22(17)37-21/h1-3,6-9,12,15H,4-5,10-11,13-14H2,(H,34,35)
|
| Chemical Name |
3-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]spiro[6H-[1]benzoxepino[3,2-b]pyridine-5,1'-cyclopropane]-9-carboxylic acid
|
| HS Tariff Code |
2934.99.9001
|
| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
|
| Solubility (In Vitro) |
DMSO: ~100 mg/mL (~182.0 mM; with ultrasonication)
|
|---|---|
| Solubility (In Vivo) |
Solubility in Formulation 1: 5 mg/mL (9.10 mM) in 10% DMSO + 40% PEG300 + 5% Tween-80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), Clear solution; with ultrasonication and warming and heat to 80°C.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of DMSO stock solution (50.0 mg/mL) to 400 μL of PEG300 and mix well; then add 50 μL of Tween-80 and mix well; finally add 450 μL of physiological saline and adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: 5 mg/mL (9.10 mM) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), Clear solution; with ultrasonication. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of DMSO stock solution (50.0 mg/mL) to 900 μL of corn oil and mix well. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.8202 mL | 9.1008 mL | 18.2017 mL | |
| 5 mM | 0.3640 mL | 1.8202 mL | 3.6403 mL | |
| 10 mM | 0.1820 mL | 0.9101 mL | 1.8202 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
Link: https://clinicaltrials.gov/ct2/show/NCT05397379
Conditions:Non-Alcoholic SteatohepatitisLink: https://clinicaltrials.gov/ct2/show/NCT04546984
Conditions:Nonalcoholic Steatohepatitis (NASH)Link: https://clinicaltrials.gov/ct2/show/NCT04422496
Conditions:Non-alcoholic Fatty Liver Disease|Non-alcoholic Steatohepatitis
Title:The Tolerability , Pharmacokinetics and Pharmacodynamics Study of HEC96719 Tablets in Healthy Adult Subjects
Status:Completed
updateDate:2020-12-28
Ctid:NCT04194242
Link: https://clinicaltrials.gov/ct2/show/NCT04194242
Conditions:Nonalcoholic Steatohepatitis (NASH)Products are for research use only; We do not sell to patients
Copyright 2020 InvivoChem LLC | All Rights Reserved
