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| 1mg |
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| 5mg |
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| 10mg | |||
| Other Sizes |
| Targets |
Thyrotropin receptor (TSHR). TSHR antagonist S37a binds directly to the TSHR. It is an inverse agonist capable of inhibiting the constitutive activity of the receptor. It blocks the activation of TSHR by multiple agonists, including thyrotropin (TSH) itself, the human monoclonal antibody M22, the murine monoclonal antibody KSAb1, and the small-molecule agonist C2. This broad antagonism effectively inhibits the downstream signaling cascade mediated by G proteins. In vitro, it inhibits cAMP accumulation with an IC₅0 of ~20 microM (hTSHR).
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| ln Vitro |
TSHR is inhibited by the TSHR antagonist S37a. The half-life of mTSHR and hTSHR in HEK293 cells is 40 µM and roughly 20 µM, respectively [1]. The TSHR antagonist S37a blocks not only the thyrotropin-induced activation of TSHR but also the activation of the allosteric small molecule agonist C2, the human monoclonal TSAb M22, and the mouse monoclonal KSAb1 [1].
S37a exhibits direct inhibition of TSHR activity in HEK293 cells stably expressing the receptor. The IC₅0s are 40 microM for mouse TSHR and approximately 20 microM for human TSHR. This selectivity and potency confirm that the compound can disrupt TSH-induced cyclic adenosine monophosphate (cAMP) formation, which is the primary second messenger signaling pathway for TSHR. It also inhibits cAMP formation stimulated by monoclonal TSHR autoantibodies (M22 and KSAb1) and the allosteric agonist C2. |
| ln Vivo |
The TSHR antagonist S37a also inhibits cyclic adenosine monophosphate production via an oligoclonal TSAb that is substantially abundant in the sera of GO patients [1]. The TSHR antagonist S37a (10 mg/kg; ig) demonstrates no toxicity in mice and has an oral bioavailability of up to 53% [1].
S37a inhibits the cyclic AMP formation induced by oligoclonal TSAb found in the sera of Graves‘ orbitopathy patients. At an oral dose of 10 mg/kg via intragastric (i.g.) administration in SWISS (CD1) mice, S37a displays no observable toxicity and demonstrates a remarkable oral bioavailability of 53%. Its ability to block TSHR activation in vivo is evidenced by the reduction of cAMP formation induced by TSAb, validating its potential as a therapeutic candidate for GO by preventing the stimulatory effects of pathogenic autoantibodies. |
| Enzyme Assay |
To measure direct receptor binding, a competition binding assay is used. Membranes from TSHR-expressing CHO cells are incubated with [¹2⁵I]-labeled bovine TSH (bTSH) and varying concentrations of S37a (0-200 microM) for 2 hours at room temperature. Non-specific binding is determined with unlabeled bTSH. Bound radioactivity is separated by filtration through glass fiber filters, and the radioactivity is counted. To assess functional antagonism, an ELISA-based cAMP assay is performed using HEK293-TSHR cells treated with TSH and the compound.
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| Cell Assay |
HEK293 cells stably expressing human TSHR are seeded in 96-well plates. The next day, cells are treated with TSHR antagonist S37a (serial dilutions ranging from 0.1-200 microM) and then stimulated with 0.1 mU/mL bovine TSH for 30 min. The reaction is stopped by cell lysis. The levels of intracellular cyclic AMP (cAMP) are measured using a competitive ELISA kit according to the manufacturer's protocol. The absorbance is read at 450 nm. The IC₅0 for cAMP inhibition by S37a is calculated from the dose-response curve.
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| Animal Protocol |
Animal/Disease Models: SWISS (CD1) mice (38-43 g) [1]
Doses: 10 mg/kg Route of Administration: po (oral gavage) Experimental Results: Oral bioavailability is as high as 53%, and the half-life after oral administration is 2.9 hrs (hrs (hours)). The in vivo protocol uses SWISS (CD1) mice weighing 38-43 g. TSHR antagonist S37a is formulated in a vehicle (e.g., 10% DMSO, 40% PEG300, 5% Tween-80, 45% saline) and administered at a dose of 10 mg/kg via oral gavage (i.g.). Blood samples are collected at various time points (0, 0.5, 1, 2, 4, 8, 12, 24 hours). Plasma is separated, and the compound concentration is analyzed by LC-MS/MS. Mice are observed for signs of toxicity for 7-14 days post-dose. Animals are then euthanized for gross necropsy. |
| ADME/Pharmacokinetics |
S37a displays an oral bioavailability of 53% in mice after oral administration at a dose of 10 mg/kg. The half-life (t1/2) of S37a after oral application is 2.9 hours. DMSO solubility is 100 mg/mL, supporting in vivo formulation. The compound has a molecular weight of 460.57. These properties indicate a favorable pharmacokinetic profile as an oral agent, with sufficient exposure to allow for once or twice-daily dosing to maintain target engagement and therapeutic effect in animal models of GO.
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| Toxicity/Toxicokinetics |
S37a displays no observable toxicity in SWISS (CD1) mice when administered at a single oral dose of 10 mg/kg. No clinical signs of toxicity, significant weight loss, or mortality were reported during the study duration. Following the experiment, animals were euthanized and underwent gross necropsy; no macroscopic abnormalities were detected in major organs. These data suggest a favorable acute safety profile. However, repeated-dose toxicology studies would be required for further clinical development.
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| References | |
| Additional Infomation |
TSHR antagonist S37a is a preclinical research tool compound and is not an approved drug. It is specifically designed for studying the pathophysiology of Graves‘ Orbitopathy (GO). While it demonstrates promising oral bioavailability and efficacy in blocking TSHR activation, it has not yet progressed into human clinical trials. It is a selective, small-molecule antagonist that offers an alternative to biological drugs (monoclonal antibodies) for treating GO, providing a pharmacological tool to control the disease at the receptor level.
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| Molecular Formula |
C25H19N2O3S2
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|---|---|
| Molecular Weight |
459.5600
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| Exact Mass |
460.091
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| CAS # |
2143452-20-2
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| Related CAS # |
TSHR antagonist S37b;2143452-22-4
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| PubChem CID |
132083268
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| Appearance |
Off-white to light yellow solid powder
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| LogP |
3.8
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
5
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| Rotatable Bond Count |
2
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| Heavy Atom Count |
32
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| Complexity |
907
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| Defined Atom Stereocenter Count |
7
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| SMILES |
S1C2=C([C](C3C([H])=C([H])C([H])=C([H])C=3[H])[C@@]3([H])[C@]1([H])[C@@]1([H])C([H])([H])[C@]3([H])[C@@]3([H])C(N(C4C([H])=C([H])C([H])=C([H])C=4[H])C([C@@]13[H])=O)=O)SC(N2[H])=O |^1:3|
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| InChi Key |
YGFJFPYQZCZNIH-HSXTZPDUSA-N
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| InChi Code |
InChI=1S/C25H20N2O3S2/c28-23-18-14-11-15(19(18)24(29)27(23)13-9-5-2-6-10-13)20-17(14)16(12-7-3-1-4-8-12)21-22(31-20)26-25(30)32-21/h1-10,14-20H,11H2,(H,26,30)/t14-,15-,16-,17-,18+,19-,20-/m0/s1
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| Chemical Name |
(1S,2S,9R,10S,11R,12R,16R)-9,14-diphenyl-3,7-dithia-5,14-diazapentacyclo[9.5.1.02,10.04,8.012,16]heptadec-4(8)-ene-6,13,15-trione
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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 : ~100 mg/mL (~217.12 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (5.43 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 25.0 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: 2.5 mg/mL (5.43 mM) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. View More
Solubility in Formulation 3: ≥ 2.5 mg/mL (5.43 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.1760 mL | 10.8800 mL | 21.7599 mL | |
| 5 mM | 0.4352 mL | 2.1760 mL | 4.3520 mL | |
| 10 mM | 0.2176 mL | 1.0880 mL | 2.1760 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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