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| Targets |
The primary target of DS28120313 is the regulatory pathway that controls hepcidin production, particularly the signaling cascade induced by the pro-inflammatory cytokine interleukin-6 (IL-6). Hepcidin expression is transcriptionally regulated by several factors, with the IL-6/STAT3 pathway being a major driver during inflammation. In response to IL-6 signaling, STAT3 is phosphorylated and translocates to the nucleus to activate the hepcidin promoter. While DS28120313's exact molecular target is not explicitly stated, its mechanism is defined by its ability to suppress the production of hepcidin. By inhibiting hepcidin production, it counteracts the iron-restrictive state caused by inflammation, allowing for increased iron availability for red blood cell production.
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| ln Vitro |
DS28120313 is a potent inhibitor of hepcidin production, with an IC₅₀ of 0.093 μM (93 nM). This high level of potency indicates that it is effective at very low concentrations. Its in vitro activity is typically assessed by measuring hepcidin levels in cell culture models, such as primary hepatocytes or hepatoma cell lines (e.g., HepG2 or Huh7 cells) that produce hepcidin. In these assays, cells are stimulated with IL-6 or other inducers of hepcidin expression, and the compound's ability to reduce hepcidin production is measured by ELISA or quantitative PCR (qPCR) for hepcidin mRNA. The compound demonstrates strong potency in inhibiting this response.
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| ln Vivo |
In a C57BL/6 mouse model of IL-6-induced acute inflammation, DS28120313 (oral; 30 mg/kg; 30 minutes before IL-6) inhibits hepcidin synthesis and lowers blood hepcidin levels [1].
DS28120313 has demonstrated in vivo activity in mouse models. In a key study, the compound was administered orally at a dose of 30 mg/kg, 30 minutes prior to IL-6 administration, in an IL-6-induced acute inflammatory C57BL/6 mouse model. This treatment effectively inhibited hepcidin production and decreased the blood hepcidin level compared to control animals. This in vivo validation is crucial for demonstrating that the compound's in vitro activity translates into a functional effect in a living organism, confirming its potential as a therapeutic agent for conditions of iron-restricted erythropoiesis. |
| Enzyme Assay |
The in vitro assay protocol for DS28120313 typically involves measuring the inhibition of IL-6-induced hepcidin production in hepatocyte cultures. Human hepatoma cells (e.g., HepG2) are seeded in multi-well plates and treated with varying concentrations of DS28120313. After a period of incubation, the cells are stimulated with IL-6 to induce hepcidin expression. Following further incubation, the cell culture supernatant is collected, and the concentration of hepcidin is measured using a specific ELISA. Alternatively, RNA is extracted from the cells, and hepcidin mRNA levels are quantified by qPCR. The reduction in hepcidin levels in the presence of the compound is a direct measure of its inhibitory activity, and an IC₅₀ value can be calculated.
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| Cell Assay |
In vitro cell-based assays for DS28120313 are essentially the same as the enzyme/receptor assays described above, as the readout is the inhibition of hepcidin production in hepatocytes. These assays are the primary means of characterizing the compound's cellular activity. There are no standard cell viability assays for this compound, as its mechanism is not directly cytotoxic.
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| Animal Protocol |
The in vivo animal study for DS28120313 is well-defined and serves as a key proof-of-concept experiment. In the IL-6-induced acute inflammatory C57BL/6 mouse model, mice are first treated orally with DS28120313 at a dose of 30 mg/kg. Thirty minutes later, they receive an injection of IL-6 to induce an acute inflammatory state and stimulate hepcidin production. A control group receives vehicle instead of the compound. After a period of time (e.g., a few hours), blood samples are collected, and the concentration of hepcidin in the serum is measured by ELISA. The study demonstrates that DS28120313 can effectively suppress the IL-6-induced increase in hepcidin levels, confirming its mechanism of action in vivo.
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| ADME/Pharmacokinetics |
DS28120313 is an orally active compound, a critical feature for a potential therapeutic for chronic conditions. Its molecular weight is 311.34. While detailed pharmacokinetic parameters are not provided in the search results, its designation as orally active implies it has favorable ADME properties. Its efficacy in an in vivo mouse model confirms that it reaches sufficient systemic concentrations to exert its pharmacological effect.
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| Toxicity/Toxicokinetics |
Specific toxicity data for DS28120313 is not publicly available. As an inhibitor of hepcidin production, its primary effect would be to increase iron availability. While this is the intended therapeutic effect, excessive iron accumulation could be a potential safety concern. The compound is classified as a research tool and is not intended for human use. Any future development would require extensive toxicology studies to assess its safety profile.
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| References |
[1]. Fukuda T, et al. Discovery of DS28120313 as a potent orally active hepcidin production inhibitor: Design and optimization of novel 4,6-disubstituted indazole derivatives. Bioorg Med Chem Lett. 2017 Dec 1;27(23):5252-5257.
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| Additional Infomation |
DS28120313 is a research compound being developed as a novel therapeutic for anemias of chronic disease and other conditions characterized by iron-restricted erythropoiesis due to elevated hepcidin. Its ability to orally suppress hepcidin production makes it a promising drug candidate. The compound has not yet received FDA approval and is currently in the preclinical research stage.
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| Molecular Formula |
C16H17N5O2
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| Molecular Weight |
311.338482618332
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| Exact Mass |
311.138
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| CAS # |
2146177-09-3
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| PubChem CID |
138109938
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| Appearance |
Off-white to light yellow solid powder
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| LogP |
2
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| Hydrogen Bond Donor Count |
3
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| Hydrogen Bond Acceptor Count |
4
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| Rotatable Bond Count |
4
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| Heavy Atom Count |
23
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| Complexity |
458
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| Defined Atom Stereocenter Count |
0
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| SMILES |
CC1=C(C(=NN1)C2CC2)C3=CC4=C(C=NN4)C(=C3)NC(=O)OC
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| InChi Key |
QTYLFQMDDFBRTJ-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C16H17N5O2/c1-8-14(15(21-19-8)9-3-4-9)10-5-12(18-16(22)23-2)11-7-17-20-13(11)6-10/h5-7,9H,3-4H2,1-2H3,(H,17,20)(H,18,22)(H,19,21)
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| Chemical Name |
methyl N-[6-(3-cyclopropyl-5-methyl-1H-pyrazol-4-yl)-1H-indazol-4-yl]carbamate
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| Synonyms |
DS 28120313; DS-28120313; DS28120313
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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 : ~12.5 mg/mL (~40.15 mM)
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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 | 3.2119 mL | 16.0596 mL | 32.1192 mL | |
| 5 mM | 0.6424 mL | 3.2119 mL | 6.4238 mL | |
| 10 mM | 0.3212 mL | 1.6060 mL | 3.2119 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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