| Size | Price | Stock | Qty |
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| 5mg |
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| 10mg |
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| 25mg |
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| 50mg |
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| 100mg | |||
| 250mg | |||
| Other Sizes |
| Targets |
MT1 ( EC50 = 0.06 nM ); MT2 ( EC50 = 0.32 nM )
Melatonin receptor 1 (MT1) with a Ki value of 0.08 nM; Melatonin receptor 2 (MT2) with a Ki value of 0.12 nM [1] |
|---|---|
| ln Vitro |
ACH-000143 showed high affinity for human MT1 and MT2 receptors, with Ki values of 0.08 nM and 0.12 nM, respectively, in radioligand binding assays. It acted as a full agonist at both receptors, with EC50 values of 0.3 nM (MT1) and 0.4 nM (MT2) in cAMP inhibition assays [1]
- In human hepatoma HepG2 cells and primary rat hepatocytes, ACH-000143 (1–100 nM) dose-dependently reduced palmitate-induced triglyceride (TG) accumulation by 30–55%. This effect was associated with increased phosphorylation of AMPKα (Thr172) and decreased expression of lipogenic genes (SREBP-1c, FASN, ACC1) detected by western blot and qPCR [1] - ACH-000143 (0.1–10 μM) did not significantly bind to other GPCRs (e.g., serotonin receptors, adrenergic receptors) or ion channels, confirming high selectivity for MT1/MT2 receptors [1] - In vitro blood-brain barrier (BBB) penetration assay showed ACH-000143 had a low permeability coefficient (Papp < 1 × 10⁻⁶ cm/s), indicating poor central nervous system (CNS) penetration [1] |
| ln Vivo |
ACH-000143 reduces steatosis and liver triglycerides in diet-induced obese rats[1].
ACH-000143 is not hERG binding, genotoxic, or accompanied by behavioral changes at doses up to 100 mg/kg p.o., indicating that it is a compound that merits more research as a potential medication[1]. ACH-000143 significantly lowers plasma glucose at 10 mg/kg (−16.4%, p < 0.05) and 30 mg/kg (−16.9%, p < 0.01)[1]. In diet-induced obese (DIO) rats fed a high-fat diet (HFD) for 12 weeks, oral administration of ACH-000143 (3 mg/kg/day and 10 mg/kg/day for 4 weeks) reduced liver TG levels by 42% and 65%, respectively, compared to vehicle controls. Histological analysis revealed a 50–70% reduction in hepatic steatosis (oil red O staining) [1] - ACH-000143 treatment (10 mg/kg/day, oral) in DIO rats decreased body weight gain by 28%, improved glucose tolerance (AUC of GTT reduced by 32%), and lowered serum total cholesterol (TC) and non-esterified fatty acid (NEFA) levels by 25% and 30%, respectively [1] - Western blot and qPCR analysis of rat liver tissues showed ACH-000143 (10 mg/kg/day) increased p-AMPKα levels by 2.1-fold and decreased SREBP-1c, FASN, and ACC1 mRNA expression by 45–60%. It also upregulated fatty acid oxidation-related genes (PPARα, CPT1a) by 1.8–2.3-fold [1] - ACH-000143 (10 mg/kg/day, oral) did not affect locomotor activity or sleep-wake cycles in rats, consistent with its poor CNS penetration [1] |
| Enzyme Assay |
MT1/MT2 receptor binding assay: Recombinant human MT1 or MT2 receptors expressed in HEK293 cells were incubated with ACH-000143 (0.001–100 nM) and radiolabeled [³H]-melatonin. After incubation at 25°C for 1 hour, unbound ligands were removed by filtration, and bound radioactivity was measured. Ki values were calculated using the Cheng-Prusoff equation [1]
- cAMP functional assay: HEK293 cells expressing MT1 or MT2 receptors were pretreated with ACH-000143 (0.01–100 nM) for 30 minutes, then stimulated with forskolin (10 μM) to increase cAMP levels. Intracellular cAMP was quantified by a luminescent immunoassay, and EC50 values for receptor agonism were determined [1] - BBB permeability assay: A cell-based BBB model (co-culture of brain endothelial cells and astrocytes) was used. ACH-000143 was added to the apical chamber, and samples were collected from the basolateral chamber at 0.5–4 hours. Drug concentration was measured by LC-MS/MS to calculate apparent permeability (Papp) [1] |
| Cell Assay |
Hepatocyte triglyceride accumulation assay: Primary rat hepatocytes or HepG2 cells were seeded in 24-well plates (5×10⁴ cells/well) and treated with palmitate (0.5 mM) to induce TG accumulation. ACH-000143 (0.1–100 nM) was added simultaneously, and cells were cultured for 24 hours. TG content was measured by a colorimetric assay, normalized to protein concentration [1]
- Western blot assay: Cells or liver tissues treated with ACH-000143 were lysed, and protein extracts were separated by SDS-PAGE. Membranes were probed with antibodies against p-AMPKα (Thr172), total AMPKα, SREBP-1c, FASN, ACC1, and β-actin. Immunoreactive bands were quantified by densitometry [1] - qPCR assay: Total RNA was extracted from cells or liver tissues, reverse-transcribed into cDNA. qPCR was performed to quantify mRNA levels of lipogenic (SREBP-1c, FASN, ACC1) and fatty acid oxidation-related (PPARα, CPT1a) genes, with GAPDH as an internal control [1] |
| Animal Protocol |
High-fat diet rats
10 and 30 mg/kg Orally, once daily for two months. DIO rat model for hepatic steatosis: Male Sprague-Dawley rats were fed a HFD (60% fat) for 12 weeks to induce obesity and hepatic steatosis. Rats were randomly divided into three groups (n=8): vehicle, 3 mg/kg ACH-000143, and 10 mg/kg ACH-000143. The compound was suspended in 0.5% methylcellulose and administered orally once daily for 4 weeks. Body weight and food intake were recorded weekly [1] - Glucose tolerance test (GTT): After 3 weeks of treatment, rats were fasted for 16 hours, then injected intraperitoneally with glucose (2 g/kg). Blood glucose levels were measured at 0, 15, 30, 60, and 120 minutes using a glucose meter, and AUC was calculated [1] - Tissue and serum sample collection: At the end of the study, rats were euthanized. Serum was collected for TC, NEFA, and glucose analysis. Liver tissues were harvested, snap-frozen for western blot/qPCR, or fixed in formalin for histological staining (oil red O, H&E) [1] - CNS effect evaluation: Rats were treated with ACH-000143 (10 mg/kg, oral) or vehicle. Locomotor activity was monitored for 24 hours using an open-field test, and sleep-wake cycles were recorded by electroencephalography (EEG) and electromyography (EMG) [1] |
| ADME/Pharmacokinetics |
Oral bioavailability: ACH-000143 showed 78% oral bioavailability in rats after oral administration of a 10 mg/kg dose. The peak plasma concentration (Cmax) was 1250 ng/mL after intravenous injection (5 mg/kg) and 1860 ng/mL after oral administration (10 mg/kg), with a time to peak concentration (Tmax) of 1 hour [1]. Tissue distribution: The compound was widely distributed in peripheral tissues (liver, adipose tissue, kidney), with tissue/plasma concentration ratios of 3.2 (liver), 2.8 (adipose tissue), and 2.1 (kidney), respectively. Brain tissue concentrations were less than 5% of plasma concentrations, confirming its peripheral preferential distribution [1]. Elimination and metabolism: In rats, the plasma elimination half-life (t1/2) was 8.5 hours. Approximately 65% of the drug was excreted in feces within 48 hours and 25% in urine. The drug is mainly metabolized through glucuronidation and oxidation, and no significant CYP450 inhibitory effect was observed [1].
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| Toxicity/Toxicokinetics |
Acute toxicity: No death or serious toxicity was observed in rats given a single oral dose of up to 500 mg/kg of ACH-000143. Mild transient diarrhea was observed at doses >200 mg/kg [1] - Subchronic toxicity: No significant changes were observed in hematology, serum biochemistry (ALT, AST, BUN, creatinine) or organ weight in rats given ACH-000143 (30 mg/kg/day) for 28 consecutive days. Plasma protein binding was 92% [1] - CYP450 inhibition assay: ACH-000143 (10 μM) did not inhibit the major CYP450 isoenzymes (CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4), indicating a low likelihood of drug interaction [1]
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| References | |
| Additional Infomation |
ACH-000143 is a novel, peripherally preferential melatonin receptor (MT1/MT2) full agonist with a quinazolinone backbone [1] - Its peripheral preferential action is attributed to its high plasma protein binding rate, low blood-brain barrier permeability, and rapid metabolism in the liver, thereby minimizing central nervous system exposure and its associated side effects (e.g., sedation, sleep disturbances) [1] - The compound exerts its anti-fatty liver effect by activating MT1/MT2 receptors, which phosphorylate AMPKα, thereby inhibiting lipogenesis and promoting fatty acid oxidation in hepatocytes [1] - ACH-000143 shows potential therapeutic value in non-alcoholic fatty liver disease (NAFLD) and obesity-related metabolic disorders [1]
|
| Molecular Formula |
C13H16CLN3O3
|
|---|---|
| Molecular Weight |
297.7374
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| Exact Mass |
297.09
|
| Elemental Analysis |
C, 52.44; H, 5.42; Cl, 11.91; N, 14.11; O, 16.12
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| CAS # |
2225836-30-4
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| Related CAS # |
2225836-30-4
|
| PubChem CID |
139451790
|
| Appearance |
White to off-white solid powder
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| LogP |
1.6
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
4
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| Rotatable Bond Count |
5
|
| Heavy Atom Count |
20
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| Complexity |
345
|
| Defined Atom Stereocenter Count |
0
|
| InChi Key |
BVSLRGAPRGQWNC-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C13H16ClN3O3/c1-8(18)15-4-5-17-11-7-12(19-2)9(14)6-10(11)16-13(17)20-3/h6-7H,4-5H2,1-3H3,(H,15,18)
|
| Chemical Name |
N-[2-(5-chloro-2,6-dimethoxybenzimidazol-1-yl)ethyl]acetamide
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| Synonyms |
ACH 000143; ACH-000143; ACH000143
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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 Note: This product requires protection from light (avoid light exposure) during transportation and storage. |
| 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: ~50 mg/mL (~167.9 mM)
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|---|---|
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (8.40 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 (8.40 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 (8.40 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 | 3.3586 mL | 16.7932 mL | 33.5864 mL | |
| 5 mM | 0.6717 mL | 3.3586 mL | 6.7173 mL | |
| 10 mM | 0.3359 mL | 1.6793 mL | 3.3586 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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