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SCD1 inhibitor-4 is a novel, potent, and orally bioactive stearoylCoA desaturase-1 (SCD1) inhibitor with a favorable pharmacokinetic profile to allow for sustained SCD inhibition in vivo.
| Targets |
SCD1 (Stearoyl-CoA Desaturase-1) (IC50: 8 nM for human SCD1 enzyme activity; IC50: 12 nM for mouse SCD1 enzyme activity) [1]
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|---|---|
| ln Vitro |
Inhibition of SCD1 enzyme activity
SCD1 inhibitor-4 (1–100 nM) dose-dependently inhibited recombinant human and mouse SCD1. At 8 nM (human SCD1 IC50) and 12 nM (mouse SCD1 IC50), it reduced enzyme activity by 50%. At 50 nM, inhibition rates reached 90% (human) and 87% (mouse), as measured by detecting the conversion of stearoyl-CoA to oleoyl-CoA (HPLC-based assay) [1] - Antiproliferative activity in adipocyte precursor cells In 3T3-L1 preadipocytes, SCD1 inhibitor-4 (0.1–10 μM) suppressed cell proliferation with an IC50 of 0.8 μM (MTT assay). At 2 μM, it reduced adipocyte differentiation by 65% (oil red O staining) and decreased the oleic acid/stearic acid (C18:1/C18:0) ratio by 72% (GC-MS analysis of cellular fatty acids) [1] - Modulation of lipid metabolism in hepatocytes In HepG2 human hepatocytes, SCD1 inhibitor-4 (1–5 μM) dose-dependently reduced intracellular triglyceride accumulation by 35–58% (colorimetric assay). It also downregulated mRNA expression of lipogenic genes (SREBP-1c, FASN) by 42–53% (qPCR) and increased the expression of fatty acid oxidation-related gene PPARα by 1.8-fold (5 μM) [1] |
| ln Vivo |
Desaturation index decreased in a dose-dependent manner with SCD1 inhibitor-4 (1~30 mg/kg) showing a 55% decrease at 1 mg/kg and an 85% decrease at 10 and 30 mg/kg doses [1].
Anti-obesity and hypoglycemic efficacy in db/db mice Male db/db mice (8–10 weeks old) were treated with SCD1 inhibitor-4 (10, 30 mg/kg, oral gavage) once daily for 21 days. The 30 mg/kg dose reduced body weight by 18% and food intake by 12% compared to vehicle. Fasting blood glucose decreased by 45%, and HbA1c levels reduced by 32% (enzymatic assay). Serum triglycerides and total cholesterol were lowered by 41% and 35% respectively [1] - Improvement of insulin sensitivity In the same db/db mouse model, SCD1 inhibitor-4 (30 mg/kg) enhanced insulin sensitivity, as demonstrated by a 39% increase in glucose infusion rate during hyperinsulinemic-euglycemic clamp. Liver triglyceride content was reduced by 52% (HPLC assay), and hepatic steatosis was alleviated (histological analysis, Oil Red O staining) [1] - Dose-dependent lipid modulation At 10 mg/kg, SCD1 inhibitor-4 reduced serum triglycerides by 28% and liver triglycerides by 31%, while the 30 mg/kg dose showed more potent effects, consistent with its dose-dependent in vitro activity [1] |
| Enzyme Assay |
SCD1 enzyme activity assay
Recombinant human/mouse SCD1 protein was incubated with SCD1 inhibitor-4 (0.001–100 nM) in reaction buffer containing stearoyl-CoA (substrate) and NADPH (cofactor) at 37°C for 45 minutes. The reaction was terminated, and the product (oleoyl-CoA) was separated by HPLC. The peak area of oleoyl-CoA was quantified to calculate enzyme activity inhibition rate and IC50 values [1] - SCD1 selectivity assay SCD1 inhibitor-4 (1 μM) was tested against other fatty acid desaturases (SCD2, FADS1, FADS2). It showed >100-fold selectivity for SCD1, with no significant inhibition (<10%) of other desaturases [1] |
| Cell Assay |
3T3-L1 preadipocyte proliferation and differentiation assay
3T3-L1 cells were seeded in 96-well plates (5×10³ cells/well) and cultured overnight. SCD1 inhibitor-4 (0.1–10 μM) was added, and cells were incubated for 72 hours to assess proliferation (MTT assay). For differentiation assay, cells were treated with the inhibitor during adipogenic induction (10 days), stained with oil red O, and the absorbance was measured to quantify lipid accumulation [1] - HepG2 hepatocyte lipid metabolism assay HepG2 cells were seeded in 6-well plates (2×10⁵ cells/well) and cultured for 24 hours. SCD1 inhibitor-4 (1–5 μM) was added, and cells were incubated for 48 hours. Intracellular triglycerides were extracted and quantified by colorimetric assay. Total RNA was isolated for qPCR analysis of SREBP-1c, FASN, and PPARα mRNA expression [1] - Cellular fatty acid composition analysis 3T3-L1 cells treated with SCD1 inhibitor-4 (2 μM) for 48 hours were lysed, and fatty acids were extracted, methylated, and analyzed by GC-MS. The ratio of oleic acid (C18:1) to stearic acid (C18:0) was calculated to evaluate SCD1 inhibition efficacy [1] |
| Animal Protocol |
db/db mouse metabolic disorder model
Male db/db mice (25–30 g, 8–10 weeks old) were acclimated for 7 days. SCD1 inhibitor-4 was suspended in 0.5% carboxymethylcellulose sodium (CMC-Na) and administered by oral gavage at 10 mg/kg or 30 mg/kg once daily for 21 days. Vehicle group received 0.5% CMC-Na. Body weight and food intake were recorded daily. Fasting blood glucose and HbA1c were measured on days 0, 7, 14, and 21. At study end, serum lipids (triglycerides, total cholesterol) were analyzed, and liver tissues were collected for triglyceride quantification and histological staining [1] - Hyperinsulinemic-euglycemic clamp assay After 14 days of treatment, db/db mice in the 30 mg/kg group underwent hyperinsulinemic-euglycemic clamp. Insulin was infused intravenously at a constant rate, and glucose was infused to maintain euglycemia. The glucose infusion rate was measured to assess insulin sensitivity [1] |
| ADME/Pharmacokinetics |
Oral bioavailability: 47% in mice (oral dose 30 mg/kg) [1] - Plasma half-life (t1/2): 6.3 hours in mice (oral) [1] - Peak plasma concentration (Cmax): 2.9 μM 1 hour after oral administration (mice 30 mg/kg) [1] - Plasma protein binding: 91.5% (in vitro human plasma) [1] - Tissue distribution: The highest concentrations were found in the liver (5.7 μM), adipose tissue (4.2 μM), and pancreas (3.8 μM) 2 hours after oral administration (mice 30 mg/kg) [1]
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| Toxicity/Toxicokinetics |
Acute toxicity: No deaths or obvious toxic symptoms (weight loss, lethargy, diarrhea) were observed in mice after a single oral dose of up to 200 mg/kg [1] - Chronic toxicity: In repeated-dose studies over 28 days (mice: oral doses of 10, 30, and 100 mg/kg daily), no significant changes were observed in body weight, hematological parameters (white blood cells, red blood cells, platelets) or liver and kidney function indicators (ALT, AST, BUN, creatinine). Histological examination of the liver, kidneys, heart, and adipose tissue revealed no drug-related lesions [1] - No off-target toxicity: Due to its high selectivity for SCD1, no adverse effects on other metabolic enzymes or organ function have been reported [1]
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| References | |
| Additional Infomation |
Mechanism of action: SCD1 inhibitor-4 is a potent and selective SCD1 inhibitor. SCD1 is a key enzyme that catalyzes the conversion of saturated fatty acids (e.g., stearic acid) into monounsaturated fatty acids (e.g., oleic acid). By inhibiting SCD1, it can reduce de novo lipogenesis, inhibit adipocyte differentiation and proliferation, enhance fatty acid oxidation, and improve insulin sensitivity, thereby exerting anti-obesity, hypoglycemic and hypolipidemic effects [1]. - Therapeutic potential: By targeting SCD1-mediated lipid metabolism disorders, it can be used to treat metabolic diseases, including type 2 diabetes, obesity, and non-alcoholic fatty liver disease (NAFLD) [1]. - Structural features: This compound belongs to the N-benzylimidazolium carboxamide class of compounds. Its structure has been optimized to bind to the active site of SCD1, thereby achieving high efficiency and selectivity [1].
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| Molecular Formula |
C17H16F3N5O
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|---|---|
| Molecular Weight |
363.33705329895
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| Exact Mass |
363.13
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| Elemental Analysis |
C, 56.20; H, 4.44; F, 15.69; N, 19.28; O, 4.40
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| CAS # |
1295541-87-5
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| PubChem CID |
51346908
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| Appearance |
White to off-white solid powder
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| LogP |
2.7
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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 |
4
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| Heavy Atom Count |
26
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| Complexity |
503
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| Defined Atom Stereocenter Count |
0
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| InChi Key |
DUTKICDSXNUMBM-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C17H16F3N5O/c1-11-15(16(26)22-14-6-7-24(2)23-14)21-10-25(11)9-12-4-3-5-13(8-12)17(18,19)20/h3-8,10H,9H2,1-2H3,(H,22,23,26)
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| Chemical Name |
5-methyl-N-(1-methylpyrazol-3-yl)-1-[[3-(trifluoromethyl)phenyl]methyl]imidazole-4-carboxamide
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| Synonyms |
SCD1 inhibitor-4; DUN41875; DUN-41875; DUN 41875;
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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 (~275.22 mM)
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|---|---|
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (6.88 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 (6.88 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 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 (6.88 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 | 2.7522 mL | 13.7612 mL | 27.5224 mL | |
| 5 mM | 0.5504 mL | 2.7522 mL | 5.5045 mL | |
| 10 mM | 0.2752 mL | 1.3761 mL | 2.7522 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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