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| Targets |
Omesdafexor targets the farnesoid X receptor (FXR), a nuclear receptor that functions as a key regulator of bile acid, lipid, and glucose metabolism. Upon activation, FXR modulates the expression of genes involved in bile acid synthesis, enterohepatic circulation, lipid homeostasis, and inflammatory responses. Omesdafexor acts as a potent and selective FXR agonist, binding to the receptor and inducing its transcriptional activity, thereby regulating multiple metabolic pathways.
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| ln Vitro |
In vitro, Omesdafexor acts as a potent FXR agonist, activating the receptor and promoting its transcriptional activity. It enhances the expression of FXR target genes involved in bile acid detoxification, lipid metabolism, and antimicrobial defense. Studies have shown that Omesdafexor can improve intestinal barrier function by upregulating tight junction proteins and reducing pro-inflammatory cytokine production in cultured intestinal epithelial cells. These cellular activities confirm its role as a selective FXR modulator with beneficial effects on gut health and metabolism.
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| ln Vivo |
In vivo, Omesdafexor demonstrates significant pharmacological activity in animal models of liver disease and inflammatory conditions. Oral administration of Omesdafexor (0.03-0.3 mg/kg, once daily for four weeks) in combination with tofacitinib synergistically ameliorated colitis in a T-cell transfer-induced colitis model. Additionally, Omesdafexor has been shown to improve intestinal antimicrobial function, enhance gut barrier integrity, and suppress systemic inflammation, supporting its therapeutic potential for inflammatory bowel diseases and metabolic liver disorders.
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| Enzyme Assay |
For in vitro non-cell-based binding assays, a standard protocol uses a fluorescence polarization (FP) competition binding assay. Recombinant human FXR ligand-binding domain (LBD) is incubated with a fluorescent FXR ligand and varying concentrations of Omesdafexor (e.g., 0.1 nM - 10 uM) in a 96-well black plate. After incubation at room temperature for 60 minutes, the FP signal is measured using a microplate reader. The IC50 value is calculated from the dose-response curve. Alternatively, a TR-FRET coactivator recruitment assay can be used.
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| Cell Assay |
For in vitro cell-based assays, HEK293 cells stably transfected with a GAL4-FXR-LBD construct and a luciferase reporter gene are seeded in 96-well plates. After 24 hours, cells are treated with varying concentrations of Omesdafexor (0.01-10 uM) for 18-24 hours. Luciferase activity is measured using a commercially available luciferase assay kit and a luminometer. The EC50 for FXR activation is calculated from the dose-response curve. Positive controls such as GW4064 are used for comparison.
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| Animal Protocol |
For in vivo animal studies, a mouse model of adoptive T-cell transfer-induced colitis is commonly used. SCID mice are injected intraperitoneally with CD4+CD45RBhigh T cells to induce colitis. Omesdafexor is administered orally once daily at doses of 0.03, 0.1, and 0.3 mg/kg for four weeks. Control groups receive vehicle or a positive control FXR agonist. Disease progression is monitored by body weight, stool consistency, and colon length. At study endpoint, colon tissues are harvested for histological scoring, cytokine analysis by ELISA, and gene expression analysis by qPCR.
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| ADME/Pharmacokinetics |
Omesdafexor is an orally active small molecule with molecular weight 541.72 g/mol and high lipophilicity, suggesting good membrane permeability. Preliminary pharmacokinetic studies indicate that Omesdafexor exhibits moderate oral bioavailability, a half-life suitable for once-daily dosing, and a volume of distribution consistent with extensive tissue distribution. Its primary route of elimination is likely via hepatic metabolism, with potential enterohepatic recirculation due to its FXR target engagement. Detailed PK parameters are proprietary and available from the compound supplier upon request.
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| Toxicity/Toxicokinetics |
Comprehensive toxicology data for Omesdafexor is not publicly available as it is a preclinical research compound. As an FXR agonist, potential mechanism-based toxicities include pruritus (itching) and dyslipidemia (elevated LDL cholesterol), which are known class effects of FXR activation observed in clinical trials with other FXR agonists such as obeticholic acid. Standard safety pharmacology studies would include hERG assessment for cardiac safety and Ames test for genotoxicity. Acute toxicity studies in rodents would be conducted to determine the maximum tolerated dose.
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| References | |
| Additional Infomation |
Omesdafexor is a research-grade compound and is not approved for clinical use. It is also known as MET642 and is protected under patent WO2020061114. The compound has been studied in preclinical models of liver disease and metabolic inflammation, particularly for its effects on intestinal barrier function and antimicrobial defense. Its ability to synergize with tofacitinib in colitis models suggests potential combination therapy strategies for inflammatory bowel disease. Omesdafexor is an investigational new drug and has not yet entered clinical trials.
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| Molecular Formula |
C34H43N3O3
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|---|---|
| Molecular Weight |
541.72
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| Exact Mass |
541.33
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| CAS # |
2244440-85-3
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| PubChem CID |
135329968
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| Appearance |
White to off-white solid powder
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| LogP |
6.1
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
4
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| Rotatable Bond Count |
8
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| Heavy Atom Count |
40
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| Complexity |
819
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| Defined Atom Stereocenter Count |
0
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| SMILES |
C1=CC(=CC(C)=C1OC)[C@@H]1CC[C@@H](CN(C([C@@H]2CC[C@H](CC2)O)=O)C2C=CC=C(C=2)C2C=NN(C3CC3)C=2)CC1
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| InChi Key |
RPBNLMPTFCTXRQ-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C34H43N3O3/c1-23-18-28(12-17-33(23)40-2)25-8-6-24(7-9-25)21-36(34(39)26-10-15-32(38)16-11-26)31-5-3-4-27(19-31)29-20-35-37(22-29)30-13-14-30/h3-5,12,17-20,22,24-26,30,32,38H,6-11,13-16,21H2,1-2H3
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| Chemical Name |
N-[3-(1-cyclopropylpyrazol-4-yl)phenyl]-4-hydroxy-N-[[4-(4-methoxy-3-methylphenyl)cyclohexyl]methyl]cyclohexane-1-carboxamide
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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) |
May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples
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| Solubility (In Vivo) |
Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.
Injection Formulations
Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)(e.g. IP/IV/IM/SC) *Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution. Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline) Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil) Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals). View More
Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)] Oral Formulations
Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium) Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals). View More
Oral Formulation 3: Dissolved in PEG400 (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.8460 mL | 9.2299 mL | 18.4597 mL | |
| 5 mM | 0.3692 mL | 1.8460 mL | 3.6919 mL | |
| 10 mM | 0.1846 mL | 0.9230 mL | 1.8460 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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