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| 25mg |
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| Targets |
TSHR ( EC50 = 40 nM )
Thyroid stimulating hormone receptor (TSHR). ML-109 is a full agonist at TSHR, meaning it activates the receptor to the same maximum extent as the natural ligand TSH. The compound shows no activity at the related receptors FSHR (follicle-stimulating hormone receptor) or LHCGR (luteinizing hormone/choriogonadotropin receptor), demonstrating its selectivity for TSHR. As a small-molecule agonist, ML-109 can activate TSHR-mediated signaling pathways including cAMP production. |
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| ln Vitro |
ML-109 (Compound 2) exhibits no activity at FSHR or LHCGR, similar to compound 1, and is a full agonist at TSHR with an EC50 of 40 nM. There is a functional group in ML-109 called an aminal that can be broken down by hydrolysis or other processes. It has been observed that ML-109 degrades at low pH (t1/2 of ~3 h), but it is surprisingly stable at neutral and basic conditions (t1/2 of ~16 h)[1].
ML-109 (Compound 2) exhibits full agonist activity at TSHR with an EC50 of 40 nM. It shows no activity at FSHR or LHCGR, confirming its selectivity for TSHR. The compound contains an aminal functional group that can be broken down by hydrolysis or other processes. ML-109 degrades at low pH with a half-life of approximately 3 hours but is surprisingly stable at neutral and basic conditions with a half-life of approximately 16 hours. This stability profile is important for formulation and storage considerations. |
| ln Vivo |
In vivo studies have demonstrated that small-molecule TSHR agonists like ML-109 can stimulate thyroid function in human thyrocytes and mice. As an orally available compound, ML-109 represents a significant advance over peptide-based TSH therapies that require injection. The compound is intended as a pharmacological tool to study TSHR biology in thyroidal and extrathyroidal tissues. Further in vivo characterization including pharmacokinetics and efficacy in disease models would be valuable for therapeutic development.
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| Enzyme Assay |
In vitro TSHR agonist activity is assessed using cell-based reporter assays. Cells expressing TSHR and a cAMP-responsive luciferase reporter are treated with varying concentrations of ML-109 (0.1 nM - 10 μM) for 4-6 hours at 37°C. Luciferase activity is measured after addition of substrate, and luminescence is quantified. EC50 values are calculated from dose-response curves. For receptor binding assays, competition binding with radiolabeled TSH or small-molecule ligands can be performed using membrane preparations from TSHR-expressing cells. ML-109 is also evaluated for selectivity against FSHR and LHCGR using similar reporter assays.
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| Cell Assay |
Cell-based functional assays are performed using cells stably or transiently expressing human TSHR, such as HEK293-TSHR cells. Cells are plated in 96-well plates and treated with varying concentrations of ML-109 (0.1 nM - 10 μM) for 4-6 hours. cAMP accumulation is measured using a competitive ELISA or homogeneous time-resolved fluorescence (HTRF) cAMP assay. Alternatively, a luciferase reporter gene under the control of a cAMP-responsive element (CRE) is used. Luminescence or fluorescence is read using a plate reader. EC50 values are calculated by nonlinear regression. ML-109 demonstrates full agonist activity with an EC50 of 40 nM.
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| Animal Protocol |
In animal studies, ML-109 is typically administered orally or intraperitoneally to rodents. For thyroid function studies, mice are dosed with ML-109 and thyroid hormone levels (T3, T4) are measured in serum at various time points. Thyroid weight and histology may also be assessed. The compound's oral bioavailability makes it suitable for oral administration in pharmacokinetic and pharmacodynamic studies. Doses are selected based on preliminary tolerability and efficacy assessments. Endpoints include serum thyroid hormone levels, TSH levels, and thyroid tissue responses.
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| ADME/Pharmacokinetics |
ML-109 has a molecular weight of 523.58, a LogP of 5.1, and a hydrogen bond donor count of 3 and acceptor count of 6. The compound is a white to light yellow solid powder. It is orally bioavailable, making it suitable for in vivo administration. The compound contains an aminal functional group that is stable at neutral and basic pH but degrades at low pH with a half-life of approximately 3 hours. It should be stored as powder at -20°C for up to 3 years or in solution at -80°C for 6 months.
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| Toxicity/Toxicokinetics |
No specific toxicity data are documented for ML-109. As a research tool compound, it is intended for laboratory use only and is not approved for human therapeutic applications. The compound should be handled with appropriate safety precautions. Standard laboratory safety practices including the use of personal protective equipment (gloves, lab coat, safety goggles) and proper ventilation should be followed. Toxicity profiling including acute toxicity, genotoxicity, and organ-specific toxicity would be required for any therapeutic development.
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| References | |
| Additional Infomation |
N-[4-[[5-[5-hydroxy-4-oxo-3-(benzyl)-1,2-dihydroquinazolin-2-yl]-2-methoxyphenyl]methoxy]phenyl]acetamide is a member of the quinazolin class of compounds.
ML-109 is also known as CID-25246343 and has the PubChem CID 25246343. It is a quinazoline derivative with the chemical name N-[4-[[5-(3-benzyl-5-hydroxy-4-oxo-1,2-dihydroquinazolin-2-yl)-2-methoxyphenyl]methoxy]phenyl]acetamide. The compound was first reported in 2009 as a small-molecule agonist for the thyrotropin receptor that stimulates thyroid function in human thyrocytes and mice. It is the first selective and orally available small-molecule TSHR agonist and serves as a valuable pharmacological tool. It is intended for research use only. |
| Molecular Formula |
C31H29N3O5
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| Molecular Weight |
523.57906794548
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| Exact Mass |
523.21
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| Elemental Analysis |
C, 71.11; H, 5.58; N, 8.03; O, 15.28
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| CAS # |
1186649-91-1
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| Related CAS # |
ML109 HCl; 1186649-91-1
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| PubChem CID |
25246343
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| Appearance |
White to light yellow solid powder
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| LogP |
5.1
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| Hydrogen Bond Donor Count |
3
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| Hydrogen Bond Acceptor Count |
6
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| Rotatable Bond Count |
8
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| Heavy Atom Count |
39
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| Complexity |
812
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| Defined Atom Stereocenter Count |
0
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| InChi Key |
JRVXFGNCHKHBPA-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C31H29N3O5/c1-20(35)32-24-12-14-25(15-13-24)39-19-23-17-22(11-16-28(23)38-2)30-33-26-9-6-10-27(36)29(26)31(37)34(30)18-21-7-4-3-5-8-21/h3-17,30,33,36H,18-19H2,1-2H3,(H,32,35)
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| Chemical Name |
N-[4-[[5-(3-benzyl-5-hydroxy-4-oxo-1,2-dihydroquinazolin-2-yl)-2-methoxyphenyl]methoxy]phenyl]acetamide
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| Synonyms |
ML-109; ML 109; ML109; CID-25246343; CID 25246343; CID25246343
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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: ~83.3 mg/mL (~159.2 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.17 mg/mL (4.14 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 21.7 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: ≥ 2.17 mg/mL (4.14 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in 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 21.7 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: ≥ 2.17 mg/mL (4.14 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 | 1.9099 mL | 9.5496 mL | 19.0993 mL | |
| 5 mM | 0.3820 mL | 1.9099 mL | 3.8199 mL | |
| 10 mM | 0.1910 mL | 0.9550 mL | 1.9099 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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