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| Targets |
SYD5115 targets the thyrotropin receptor (TSH‑R), a GPCR expressed on the surface of thyroid follicular cells. The endogenous ligand for TSH‑R is thyroid‑stimulating hormone (TSH), which regulates thyroid hormone synthesis and secretion. In autoimmune hyperthyroidism (Graves‘ disease), stimulating autoantibodies (TSAbs) bind to the TSH‑R and cause excessive production of thyroid hormones. SYD5115 is a potent antagonist of the TSH‑R, blocking both TSH‑ and autoantibody‑induced activation. By inhibiting TSH‑R activation, it reduces the production of thyroid hormones T3 and T4.
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| ln Vitro |
SYD5115 (0.1 nM-10 μM) blocks M22-induced cAMP production with IC50s of 22 nM in rat FRTL5 and HEK293-hTSHR cells, respectively [1]. Note: M22 is a stimulatory autoantibody to the human monoclonal TSH receptor (TSHR), and another autoantibody is K1-70 (blocking) [2].
SYD5115 is a potent and selective TSH‑R antagonist with IC₅0 values of 48 nM and 62 nM for rat and human TSH‑R, respectively. In cellular assays, SYD5115 (0.1 nM‑10 microM) blocks M22‑induced cAMP production in rat FRTL5 and HEK293‑hTSHR cells with IC₅0 of 22 nM. It also blocks stimulating antibody‑induced synthesis of the thyroid hormone thyroxine (T4) in vivo after a single oral dose. The compound is an N‑acetylated dihydropyrrole pyrimidine derivative with a difluorinated spirocyclohexyl ring and a chiral carbamate group. Its discovery was described in the journal Bioorganic & Medicinal Chemistry (2023). |
| ln Vivo |
SYD5115 is an orally active TSH‑R antagonist. It blocks stimulating antibody‑induced synthesis of the thyroid hormone thyroxine (T4) in vivo after a single oral dose. In rats, oral administration of SYD5115 dose‑dependently inhibits the production of T4 induced by stimulating TSH‑R antibodies. No specific dosing information, animal model details, or efficacy data are reported in the search results. The compound has the potential to be developed as a therapeutic for Graves‘ disease.
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| Enzyme Assay |
The binding of SYD5115 to the TSH‑R is measured by standard competitive binding assays using cells expressing the human or rat TSH‑R. A radiolabeled TSH or a labeled TSH‑R antagonist is used as a tracer. For functional assays, cAMP accumulation is measured. Cells expressing TSH‑R (e.g., FRTL5 rat thyroid cells or HEK293‑hTSHR cells) are seeded in 96‑well plates. SYD5115 is added at graded concentrations (0.1 nM‑10 microM) for 15‑30 min, followed by stimulation with the TSH‑R agonist M22 (a human monoclonal autoantibody). Intracellular cAMP levels are measured by competitive ELISA. The IC₅0 of 22 nM (for inhibition of M22‑induced cAMP) is calculated from dose‑response curves.
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| Cell Assay |
For cellular assays, FRTL5 rat thyroid cells or HEK293‑hTSHR cells (stably expressing human TSH‑R) are seeded in 96‑well plates. Cells are pre‑treated with SYD5115 at graded concentrations (0.1 nM‑10 microM) for 15‑30 min, then stimulated with M22 (1‑10 microg/mL) or with bovine TSH (1‑10 mU/mL). After 15‑30 min, cells are lysed, and cAMP levels are measured by competitive ELISA. The IC₅0 values for inhibition of cAMP production are calculated. Cell viability is assessed by MTT or LDH assays. For thyroid hormone production assays, FRTL5 cells or primary thyrocytes are treated with SYD5115 and then stimulated with TSH or M22. T4 levels in the culture supernatant are measured by ELISA.
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| Animal Protocol |
For in vivo evaluation of T4 suppression, male Sprague‑Dawley rats are used. A stimulating TSH‑R antibody (e.g., M22) is administered intravenously (IV) to induce T4 production. SYD5115 is administered orally at doses of 1‑30 mg/kg, either before or after antibody administration. Blood samples are collected at 0, 2, 4, 6, 8, 12, and 24 h. Serum T4 levels are measured by ELISA. The compound blocks stimulating antibody‑induced synthesis of T4 in a dose‑dependent manner after a single oral dose. No specific protocols or detailed efficacy data are provided.
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| ADME/Pharmacokinetics |
SYD5115 (C30H33F2N₅O4, MW = 565.6, purity ≥98%, CAS 2296821‑50‑4) is a solid powder. For storage, the powder should be kept at -20 degC for up to 3 years, sealed and protected from light. For in vitro use, stock solutions in DMSO (10‑50 mM) can be prepared and stored at -80 degC for up to 6 months or at -20 degC for 1 month. For in vivo oral administration, it can be formulated in 0.5% methylcellulose/0.1% Tween‑80 or in other suitable vehicles. No detailed PK parameters are reported.
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| Toxicity/Toxicokinetics |
No specific toxicity data for SYD5115 are reported. As a research‑grade TSH‑R antagonist, it is not intended for human or veterinary use. Standard laboratory safety precautions for handling chemicals should be followed. TSH‑R antagonists may cause hypothyroidism as an on‑target effect; thyroid hormone levels should be monitored. No LD₅0 or formal toxicology studies are available.
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| References |
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| Additional Infomation |
SYD5115 is a research‑grade, orally active small‑molecule antagonist of the thyrotropin receptor (TSH‑R). Graves‘ disease is an autoimmune disorder caused by stimulating autoantibodies against the TSH‑R, leading to hyperthyroidism. Current treatments for Graves‘ disease (antithyroid drugs, radioactive iodine, surgery) have limitations. SYD5115 represents a novel therapeutic approach as a small‑molecule TSH‑R antagonist. The compound was discovered by researchers at Merck (MSD) and described in Bioorganic & Medicinal Chemistry (2023). SYD5115 is for research use only and has not received regulatory approval.
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| Molecular Formula |
C22H32F2N4O3
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| Molecular Weight |
438.51
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| Appearance |
White to off-white 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 | 2.2804 mL | 11.4022 mL | 22.8045 mL | |
| 5 mM | 0.4561 mL | 2.2804 mL | 4.5609 mL | |
| 10 mM | 0.2280 mL | 1.1402 mL | 2.2804 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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