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FGH10019 is a novel and potent inhibitor of the sterol regulatory element-binding protein (SREBP) with IC50 of 1 μM. It has high aqueous solubility and membrane permeability and may serve as a seed molecule for further development. Treatment of the CHO-K1 cells with analog FGH10019 decreases the percentage of the mature form of SREBP-2 (68 kDa) at lower concentrations than treatment with fatostatin.
| Targets |
SCAP (SREBP cleavage‑activating protein) – the direct target of fatostatin. [1]
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| ln Vitro |
The proportion of the mature form of SREBP-2 (68 kDa) in CHO-K1 cells was lowered to a lower concentration by treatment with the analog FGH10019 than by treatment with fatostatin. The IC50 of analogue FGH10019 was approximately 1 μM, which was 5–10 times lower than the IC50 of fatostatin (roughly 10 μM), according to densitometric examination of the gel [1].
- In a luciferase reporter gene assay using CHOK1 cells transfected with SRE‑responsive luciferase and β‑gal control, FGH10019 inhibited SREBP activation with an IC50 of 0.7 ± 0.2 μM (mean ± SD, n≥3). For comparison, the endogenous inhibitor 25‑hydroxycholesterol gave an IC50 of 0.3 ± 0.0 μM. [1] - Western blot analysis of SREBP‑2 in CHO‑K1 cells showed that FGH10019 reduced the percentage of the mature (68 kDa) form of SREBP‑2 at lower concentrations than fatostatin. Densitometric quantification indicated an IC50 of approximately 1 μM for FGH10019 (compared to ~10 μM for fatostatin). [1] - Real‑time RT‑PCR analysis in DU145 human prostate cancer cells demonstrated that FGH10019 downregulated all nine tested SREBP‑responsive genes (MVK, HMGCR, ACL, INSIG1, MVD, HMGCS1, IDI1, SCD1, LDLR) by at least 25%. In contrast, expression of three control genes unrelated to SREBP (RPL13A, B2M, GAPDH) was not significantly affected. [1] |
| ln Vivo |
Male ob/ob mice aged 5 weeks were fed FGH10019-treated chow at a dose rate calculated to provide approximately 23 mg/kg body weight of approximately 0.7 mg analog FGH10019 per day, with an average body weight of about 30 g. In comparison to control mice, the mice's body weight dropped by 8–9% after 8 weeks on a diet treated with analog 24 [1].
- Oral administration of FGH10019 to male ob/ob mice (fed chow containing the compound for 8 weeks, dose rate approximately 0.7 mg/day or 23 mg/kg body weight) resulted in 8‑9% less weight gain compared to control mice (37.9 ± 0.9 vs. 41.4 ± 1.1 g/mouse, P<0.05). Food intake was slightly lower in treated mice (3.4 ± 0.54 vs. 3.6 ± 0.54 g/mouse per day). [1] - Blood glucose was lower in treated mice (214 ± 16 mg/dl) than in controls (243.7 ± 27.6 mg/dl, P=0.09). [1] - Serum total cholesterol was reduced in treated mice (220 ± 11 vs. 285 ± 8 mg/dl, P<0.05). LDL level decreased by ~37% (50.2 ± 4.4 vs. 79.38 ± 2.85 mg/dl, P<0.05), while HDL level remained unchanged (164.5 ± 5.3 vs. 164.83 ± 4.5 mg/dl). [1] - Liver triglyceride content was significantly lower in FGH10019‑treated mice (28 ± 1.0 vs. 42 ± 2.0 mg/g tissue, P<0.05), indicating amelioration of fatty liver conditions. [1] |
| Cell Assay |
- Luciferase reporter assay: CHOK1 cells were co‑transfected with a reporter construct containing three repeats of sterol regulatory elements (SREs) driving luciferase expression and a control β‑galactosidase reporter driven by a constitutively active actin promoter. Cells were cultured under lipid‑depleted conditions to activate SREBP. Test compounds were added, and after incubation, luciferase activity was measured and normalized to β‑galactosidase activity. IC50 values were calculated from dose‑response curves. [1]
- Western blot analysis: CHO‑K1 cells were treated with various concentrations of FGH10019 (1, 5, 20 μM), fatostatin, or sterols (10 μg/mL cholesterol + 1 μg/mL 25‑hydroxycholesterol) for a specified period. Cell lysates were subjected to SDS‑PAGE and immunoblotted with an antibody against SREBP‑2. The precursor and mature forms of SREBP‑2 were detected and quantified by densitometry. [1] - Real‑time RT‑PCR: DU145 cells were treated with FGH10019 (concentration not explicitly stated in the method section, but results shown in Figure 4). Total RNA was isolated, reverse‑transcribed, and subjected to real‑time PCR using primers specific for nine SREBP‑responsive genes and three control genes. Expression levels were normalized to internal controls and compared to vehicle‑treated samples. [1] |
| Animal Protocol |
- Male ob/ob mice (5 weeks old, average body weight ~30 g) were fed normal chow containing FGH10019 for 8 weeks. The compound was mixed into the chow to provide a daily dose of approximately 0.7 mg per mouse (about 23 mg/kg body weight). Control mice received the same chow without the compound. Body weight and food intake were monitored and recorded daily. At the end of the experiment, serum and liver tissues were collected for analysis. [1]
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| ADME/Pharmacokinetics |
- Aqueous solubility of FGH10019 at pH 3 was >225 μM and at pH 7 was 33.0 μM (as determined by in vitro solubility assay). [1]
- Passive membrane permeability assessed by parallel artificial membrane permeability assay (PAMPA) was classified as “high” for FGH10019. Warfarin (10 μM) was used as a membrane integrity control. Retention of all tested compounds in the membrane was >90%. [1] - Intrinsic clearance rate measured in mouse hepatocytes: 137 mL/min/kg for FGH10019, with a corresponding half‑life (t1/2) of 44.4 minutes. [1] |
| References | |
| Additional Infomation |
- FGH10019 (also referred to as FGH10019) is a methanesulfonamide derivative of fatostatin. It was the most potent analog among a series of diaryl thiazole derivatives tested for inhibition of SREBP activation. [1]
- The compound demonstrates improved drug‑like properties compared to fatostatin, including higher aqueous solubility, higher membrane permeability, and moderate metabolic stability in mouse hepatocytes. [1] - FGH10019 is orally available in mice, as shown by the 8‑week feeding study in ob/ob mice. It reduced body weight gain, blood glucose, total cholesterol, LDL, and liver triglycerides without affecting HDL levels. [1] - The mode of action of FGH10019 appears similar to fatostatin: it selectively downregulates SREBP‑responsive genes and blocks the proteolytic activation of SREBP‑2, likely via interaction with SCAP. [1] |
| Molecular Formula |
C₁₈H₁₉N₃O₂S₂
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|---|---|
| Molecular Weight |
373.49
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| Exact Mass |
373.091
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| CAS # |
1046045-61-7
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| PubChem CID |
25012898
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| Appearance |
Light yellow to khaki solid powder
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| Density |
1.3±0.1 g/cm3
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| Boiling Point |
578.4±60.0 °C at 760 mmHg
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| Flash Point |
303.6±32.9 °C
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| Vapour Pressure |
0.0±1.6 mmHg at 25°C
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| Index of Refraction |
1.624
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| LogP |
3.97
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
6
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| Rotatable Bond Count |
6
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| Heavy Atom Count |
25
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| Complexity |
515
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| Defined Atom Stereocenter Count |
0
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| SMILES |
CCCC1=NC=CC(=C1)C2=NC(=CS2)C3=CC=C(C=C3)NS(=O)(=O)C
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| InChi Key |
OWAXXHRQPWGNTG-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C18H19N3O2S2/c1-3-4-16-11-14(9-10-19-16)18-20-17(12-24-18)13-5-7-15(8-6-13)21-25(2,22)23/h5-12,21H,3-4H2,1-2H3
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| Chemical Name |
N-[4-[2-(2-propylpyridin-4-yl)-1,3-thiazol-4-yl]phenyl]methanesulfonamide
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| Synonyms |
FGH-10019FGH 10019FGH10019
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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 : ≥ 38 mg/mL (~101.74 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 | 2.6774 mL | 13.3872 mL | 26.7745 mL | |
| 5 mM | 0.5355 mL | 2.6774 mL | 5.3549 mL | |
| 10 mM | 0.2677 mL | 1.3387 mL | 2.6774 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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