| Size | Price | Stock | Qty |
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| 5mg |
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| 10mg |
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| 25mg |
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| Other Sizes |
Purity: ≥98%
LY2562175 (LY-2562175) is a novel, potent and selective FXR agonist (EC50 = 193 nM) with lipid modulating activity, e.g. 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. LY2562175 promotes transcriptional activation of human FXR in a cell-based cotransfection assay with an EC50 of 193 nM (geometric mean).
| Targets |
Farnesoid X receptor (FXR) agonist (EC50 = 193 nM in cell-based cotransfection assay; relative EC50 = 121 nM in co-activator recruitment assay) [1]
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| ln Vitro |
In a cell-based co-transfection test, LY2562175 (EC50 = 193 nM) stimulates transcriptional activation of human FXR. In comparison to GW4064, LY2562175 exhibits a 93.5% efficacy in promoting peptide recruitment from the nuclear receptor interaction domain of the coactivator SRC-1, with a relative EC50 of 121 nM [1].
In a cell-based cotransfection assay using HEK293 cells transfected with a human FXR expression plasmid and a luciferase reporter plasmid, LY2562175 promoted FXR transcriptional activation with a geometric mean EC50 of 193 nM. It acted as a partial agonist, exhibiting approximately 41.3% efficacy relative to the full agonist GW4064. [1] In a biochemical assay using purified recombinant FXR ligand binding domain protein and the nuclear receptor interaction domain of the co-activator SRC-1 measured by AlphaScreen technology, LY2562175 promoted co-activator recruitment with a relative EC50 of 121 nM and 93.5% efficacy relative to GW4064. [1] LY2562175 demonstrated selectivity for FXR, as it did not promote transcriptional activation of other nuclear receptors including glucocorticoid receptor (GR), androgen receptor (AR), mineralocorticoid receptor (MR), and progesterone receptor (PR) at concentrations up to 10,000 nM. [1] |
| ln Vivo |
Serum triglycerides and cholesterol decreased in a dose-dependent manner when treated with LY2562175. LY2562175 lowered serum triglycerides by 76% and cholesterol by 80% at a dose of 10 mg/kg when compared to animals treated with a vehicle. It was found that the ED50 for serum triglycerides was 3.4 mg/kg and the ED50 for serum cholesterol was 2 mg/kg. In both the fasted and non-fasted states, LY2562175 treatment of female ZDF rats led to a dose-dependent reduction in plasma triglycerides. When LY2562175 and BRL49653 were given together at a fixed dosage, the reduction in fasting and non-fasting plasma triglycerides was even greater. In this animal model, FPLC lipoprotein fractionation revealed that LY2562175 treatment led to a significant increase in HDL-c and a decrease in vLDL-C [1].
In 8-week-old male LDL receptor null (LDLR -/-) mice fed a Western diet (high fat/high cholesterol), oral administration of LY2562175 once daily for 7 days caused a dose-dependent decrease in serum cholesterol and triglycerides. At 10 mg/kg, it decreased cholesterol by 80% and triglycerides by 76% compared to vehicle-treated controls. The ED50 for serum cholesterol reduction was 2.0 mg/kg, and for triglyceride reduction was 3.4 mg/kg. Analysis of lipoprotein subtypes showed profound reductions in VLDL and LDL cholesterol. [1] In female Zucker Diabetic Fatty (ZDF) rats, treatment with LY2562175 for 9 days resulted in a dose-dependent lowering of plasma triglycerides in both fasted and non-fasted states. FPLC analysis revealed a reduction in VLDL-cholesterol and a dramatic increase in HDL-cholesterol. At 30 mg/kg, HDL levels nearly doubled relative to vehicle controls. Co-administration with a fixed low dose of rosiglitazone (0.3 mg/kg) further lowered triglycerides. [1] |
| Enzyme Assay |
FXR Co-activator Recruitment Assay (AlphaScreen): The ability of LY2562175 to induce conformational changes in the FXR ligand binding domain (LBD) and recruit a transcriptional co-activator was measured. Purified recombinant human FXR LBD protein was co-incubated with the nuclear receptor interaction domain of the co-activator protein SRC-1. The interaction between the proteins, indicative of agonist-induced recruitment, was quantified using AlphaScreen technology. The potency (relative EC50) and efficacy of LY2562175 were determined relative to the full agonist GW4064. [1]
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| Cell Assay |
FXR Transcriptional Activation Assay (Cell-based Cotransfection): HEK293 cells were co-transfected with a plasmid expressing human FXR and a reporter plasmid containing two copies of the FXR response element (IR-1) driving luciferase expression. After transfection, cells were treated with LY2562175. FXR agonist activity was determined by measuring luciferase activity, which reflects the level of FXR-mediated transcriptional activation. The EC50 and relative efficacy (compared to GW4064) were calculated from the dose-response curve. [1]
Nuclear Receptor Selectivity Panel: The selectivity of LY2562175 was assessed using a panel of nuclear receptor co-transcriptional activation assays. The compound was tested in cell-based systems for its ability to activate glucocorticoid receptor (GR), androgen receptor (AR), mineralocorticoid receptor (MR), and progesterone receptor (PR). Activation was measured via appropriate reporter gene assays, and lack of activity at high concentrations indicated selectivity for FXR. [1] |
| Animal Protocol |
LDLR -/- Mouse Efficacy Study: Eight-week-old male LDL receptor null mice were acclimated to a high fat/high cholesterol diet (TD88137, containing 0.15% cholesterol and 42% fat) for two weeks. Mice were then divided into groups (n=6) and dosed once daily by oral gavage for 7 days with either vehicle (5% Solutol, 5% ethanol, 1% carboxymethylcellulose) or LY2562175 (sodium salt formulation) at varying doses (1, 3, 10, 30 mg/kg) in a dose volume of 5 mL/kg. On day 7, blood was collected via cardiac puncture under anesthesia for serum lipid analysis. [1]
ZDF Rat Efficacy Study: Female Zucker Diabetic Fatty (ZDF) rats were treated with LY2562175 at varying doses, rosiglitazone (0.3 mg/kg), or a combination of both, for 9 days. The specific vehicle and dosing regimen (frequency, route) were not detailed in the provided text. Blood was collected for the analysis of plasma triglycerides and lipoprotein profiling by FPLC. [1] Preclinical Pharmacokinetic Studies: Pharmacokinetic studies were conducted in Sprague Dawley rats, Beagle dogs, and Cynomolgus monkeys. For intravenous (IV) administration, LY2562175 was formulated in 5% Solutol / 5% ethanol in saline and dosed at 1 mg/kg (rat and dog) or 0.91 mg/kg (monkey). For oral (PO) administration, it was formulated in 1.0% carboxymethylcellulose / 0.25% polysorbate 80 / 0.05% antifoam in purified water and dosed at 3 mg/kg. Blood samples were collected at various time points, processed to plasma, and analyzed by LC-MS/MS. [1] |
| ADME/Pharmacokinetics |
Preclinical pharmacokinetics: In preclinical animal models, the mean terminal elimination half-life (T1/2) of LY2562175 after intravenous administration was approximately 2 to 10 hours. Clearance was low to moderate (below hepatic blood flow in each species). Oral exposure was higher in non-rodents compared to rodents. The time to peak concentration (Tmax) for each species after oral administration was 1 to 3 hours. Oral bioavailability in rats, dogs, and monkeys was 21 ± 5%, 82%, and 24 ± 3%, respectively. [1] Plasma protein binding: The free fraction (fu) of LY2562175 in rat plasma was 0.020, and the free fraction in human plasma was 0.032. [1]
Human Pharmacokinetics (Single-Dose Escalation): In a single-dose escalation study in healthy subjects (dose range 5 to 600 mg), LY2562175 was well tolerated. Peak plasma concentrations were reached on average 2 to 3 hours after administration. The increase in exposure (AUC and Cmax) was less than the dose-proportional increase. The mean elimination half-life was 16.9 to 24.2 hours over a dose range of 75 to 600 mg. The Cmax at the lipid-modulated ED50 dose in rodents was 4.62 ng/mL. [1] |
| Toxicity/Toxicokinetics |
In single-dose escalation studies in humans, LY2562175 was well tolerated in the dose range of 5 to 600 mg. [1] The free fraction of LY2562175 in plasma (protein-bound data) is shown in the ADME section. [1]
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| References | |
| Additional Infomation |
TERN-101 is currently undergoing clinical trials NCT04328077 (LIFT study: safety, tolerability, efficacy and pharmacokinetics of TERN-101 in patients with non-cirrhotic non-alcoholic steatohepatitis (NASH)). LY2562175 (chemical name: 6-(4-{[5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl]methoxy}piperidin-1-yl)-1-methyl-1H-indole-3-carboxylic acid) is a novel, potent and selective FXR agonist initially used to treat dyslipidemia and atherosclerosis. [1]
In cell assays, it has been described as a partial FXR agonist. [1] This compound significantly reduced low-density lipoprotein cholesterol and very low-density lipoprotein cholesterol while increasing high-density lipoprotein cholesterol in preclinical animal models of dyslipidemia. [1] |
| Molecular Formula |
C28H27CL2N3O4
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|---|---|
| Molecular Weight |
540.437685251236
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| Exact Mass |
539.137
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| CAS # |
1103500-20-4
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| Related CAS # |
1103500-20-4 (free acid);LY2502175 sodium;
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| PubChem CID |
25204767
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| Appearance |
White to light yellow solid powder
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| LogP |
5.5
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
6
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| Rotatable Bond Count |
7
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| Heavy Atom Count |
37
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| Complexity |
800
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| Defined Atom Stereocenter Count |
0
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| SMILES |
ClC1C=CC=C(C=1C1C(COC2CCN(C3=CC=C4C(C(=O)O)=CN(C)C4=C3)CC2)=C(C2CC2)ON=1)Cl
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| InChi Key |
RPVDFHPBGBMWID-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C28H27Cl2N3O4/c1-32-14-20(28(34)35)19-8-7-17(13-24(19)32)33-11-9-18(10-12-33)36-15-21-26(31-37-27(21)16-5-6-16)25-22(29)3-2-4-23(25)30/h2-4,7-8,13-14,16,18H,5-6,9-12,15H2,1H3,(H,34,35)
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| Chemical Name |
6-(4-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)piperidin-1-yl)-1-methyl-1H-indole-3-carboxylic acid
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| Synonyms |
LY 2562175; LY2562175; LY-2562175.
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| HS Tariff Code |
2934.99.9001
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| 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)
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| Solubility (In Vitro) |
DMSO : ~62.5 mg/mL (~115.65 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.08 mg/mL (3.85 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to 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: ≥ 2.08 mg/mL (3.85 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.8503 mL | 9.2517 mL | 18.5034 mL | |
| 5 mM | 0.3701 mL | 1.8503 mL | 3.7007 mL | |
| 10 mM | 0.1850 mL | 0.9252 mL | 1.8503 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.
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