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| 5mg |
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| 10mg |
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| Targets |
Org 274178-0 specifically targets the thyroid-stimulating hormone receptor (TSHR), a G protein-coupled receptor (GPCR) that is primarily expressed on thyroid follicular cells and plays a central role in regulating thyroid function and metabolism. As a selective TSHR antagonist, it prevents receptor activation by endogenous TSH and by pathological TSIs present in autoimmune thyroid diseases such as Graves‘ disease. The compound functions as an allosteric antagonist, as demonstrated in mechanistic studies by van Koppen et al., which revealed its nanomolar potency and unique binding mode distinct from orthosteric competitors. This allosteric mechanism allows Org 274178-0 to modulate TSHR signaling without competing directly with TSH for the orthosteric binding site.
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| ln Vitro |
In vitro biochemical assays have demonstrated that Org 274178-0 acts as a potent TSHR antagonist, with a reported pIC₅0 value of 5.03, which corresponds to an IC₅0 of approximately 9.3 microM. It dose-dependently inhibits the activation of two major downstream signaling pathways initiated by TSHR: the cAMP signaling pathway and the phospholipase C (PLC) signaling pathway. The compound effectively blocks the stimulatory effects of both physiological agonist TSH and pathological TSIs found in patients with Graves‘ disease. This dual inhibition of both Gs and Gq/11-mediated signaling distinguishes Org 274178-0 from many other TSHR modulators and highlights its potential for treating TSHR-mediated pathologies. The compound's selectivity for TSHR over other structurally related glycoprotein hormone receptors has been established in previous pharmacological studies.
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| ln Vivo |
Specific in vivo activity data for Org 274178-0 remain limited in available literature. However, the compound has been documented as having been administered in a pediatric patient in a clinical study according to the Clarivate Pharmacokinetics Datafeed, indicating that it has progressed to some level of in vivo human investigation. Based on its in vitro antagonism of TSHR and the known role of TSHR in Graves‘ disease pathogenesis, Org 274178-0 is anticipated to attenuate TSHR-mediated signaling in vivo, including reducing thyroid hormone overproduction and alleviating the autoimmune-driven stimulation characteristic of Graves' disease and Graves‘ ophthalmopathy. The compound's ability to inhibit both cAMP and PLC pathways suggests potential for comprehensive blockade of TSHR-mediated responses in relevant animal models of autoimmune hyperthyroidism. Further in vivo pharmacological characterization would be required to fully evaluate its efficacy, potency, and duration of action in living systems.
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| Enzyme Assay |
The in vitro TSHR enzyme/receptor binding assay for Org 274178-0 typically involves competition binding experiments using cell membranes expressing recombinant human TSHR. Radiolabeled TSH or a high-affinity TSHR ligand is incubated with varying concentrations of Org 274178-0 to determine its binding affinity. The functional antagonism is assessed using cAMP accumulation assays: TSHR-expressing cells are pre-incubated with Org 274178-0, then stimulated with TSH or TSIs, and intracellular cAMP levels are quantified using a competitive immunoassay or luminescence-based detection method (e.g., HTRF or AlphaScreen). pIC₅0 values are calculated from concentration-response curves by nonlinear regression. The selectivity profile is evaluated by testing the compound against other glycoprotein hormone receptors such as FSHR and LHCGR under similar conditions.
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| Cell Assay |
In vitro cell-based experiments for Org 274178-0 are conducted using TSHR-expressing cell lines, such as CHO (Chinese hamster ovary) cells stably transfected with human TSHR. Cells are seeded in multi-well plates and incubated overnight prior to treatment. A dilution series of Org 274178-0 (typically ranging from nanomolar to micromolar concentrations) is added to the cells and pre-incubated for a defined period (e.g., 15-60 minutes). Cells are then stimulated with either TSH (in the nanomolar range) or purified TSIs from Graves‘ disease patient sera. Following stimulation (typically 30-60 minutes), cells are lysed and cAMP production is quantified using a luminescence-based detection kit (such as Cisbio cAMP dynamic kit or Promega GloSensor). PLC pathway activation is assessed by measuring inositol phosphate accumulation or intracellular calcium flux using fluorescent dyes. IC₅0 or pIC₅0 values are calculated from dose-response curves.
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| Animal Protocol |
Detailed in vivo animal experimental protocols for Org 274178-0 have not been extensively documented in the available literature. Based on standard practices for small molecule TSHR antagonists, the compound would likely be evaluated in rodent models of Graves' disease, such as mice immunized with TSHR-expressing cells or plasmids to induce autoimmune hyperthyroidism. For in vivo formulation preparation, Org 274178-0 can be dissolved in DMSO followed by dilution in appropriate vehicles. Common formulation protocols for similar TSHR antagonists include: DMSO:PEG300:Tween 80:saline in a ratio of 10:40:5:45 or DMSO:corn oil in a ratio of 10:90. The recommended working concentration for animal administration would be adjusted according to the desired dose and species. Administration routes typically include intraperitoneal (IP), intravenous (IV), intramuscular (IM), or subcutaneous (SC) injections. The compound should be freshly prepared before each administration to ensure solution clarity and stability.
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| ADME/Pharmacokinetics |
Available pharmacokinetic data for Org 274178-0 indicates that this drug has been tested for pharmacokinetics in pediatric patients, as reported by the Clarivate Pharmacokinetics Datafeed, and has been administered in a pediatric patient in a clinical study. Detailed PK parameters such as half-life, volume of distribution, clearance, oral bioavailability, and protein binding remain to be fully characterized and published. As a small molecule compound with molecular weight 480.52 and calculated LogP value within a moderate range (typical for TSHR antagonists), Org 274178-0 is expected to possess reasonable membrane permeability. The chemical structure features fluorine atoms, which may contribute to improved metabolic stability. Storage recommendations include keeping the powder at -20degC for up to three years and storing in solvent at -80degC for up to one year. The compound is stable at ambient temperature for several days during ordinary shipping.
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| Toxicity/Toxicokinetics |
According to the Safety Data Sheet (SDS) for Org 274178-0, the compound is classified under GHS as having Acute Toxicity Category 4 for oral exposure (H302: Harmful if swallowed). It also exhibits Acute Aquatic Toxicity Category 1 (H400) and Chronic Aquatic Toxicity Category 1 (H410: Very toxic to aquatic life with long-lasting effects). Precautionary statements include washing skin thoroughly after handling (P264), avoiding eating, drinking, or smoking during product use (P270), avoiding release to the environment (P273), and collecting spillage (P391). In case of accidental ingestion, call a poison center or physician if feeling unwell (P301+P312), rinse mouth (P330), and do NOT induce vomiting. During combustion, the compound may emit irritant fumes, and firefighters should wear self-contained breathing apparatus and protective clothing. Comprehensive repeated-dose toxicology and carcinogenicity studies have not been published. Org 274178-0 is not intended for human therapeutic use.
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| References | |
| Additional Infomation |
Org 274178-0 is a research-grade compound currently not approved by any regulatory authority (FDA, EMA, PMDA) for human therapeutic use. It is exclusively intended for in vitro and in vivo scientific research applications. The mechanism of action involves selective antagonism of the thyroid-stimulating hormone receptor (TSHR) with an allosteric mode of binding, as reported in the primary literature by van Koppen et al. in the British Journal of Pharmacology (2012). This compound is considered promising for research into Graves' disease and Graves' ophthalmopathy, autoimmune conditions driven by TSHR-activating autoantibodies. While a pediatric pharmacokinetic study has been documented, comprehensive clinical trial data remains unavailable.
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| Molecular Formula |
C28H27F3N2O2
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| Molecular Weight |
480.52
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| Related CAS # |
Org 274179-0
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| Appearance |
Light brown to brown solid powder
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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 | 2.0811 mL | 10.4054 mL | 20.8108 mL | |
| 5 mM | 0.4162 mL | 2.0811 mL | 4.1622 mL | |
| 10 mM | 0.2081 mL | 1.0405 mL | 2.0811 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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