| Size | Price | Stock | Qty |
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| 10mg |
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| 25mg |
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| 50mg |
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| Other Sizes |
| Targets |
Zamicastat targets dopamine β-hydroxylase (DβH), the enzyme that catalyzes the conversion of dopamine to norepinephrine. By inhibiting DβH, it increases levels of norepinephrine and decreases levels of dopamine in tissues. It also acts as a concentration-dependent dual inhibitor of P-gp and BCRP, which may affect drug transport and distribution.
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| ln Vitro |
After 4 hours of incubation (5, 10, 20, 50, 80, 100 μM), a significant reduction of cell viability was confirmed with 100 μM Zamicastat (p=0.010) in MDCK-BCRP cells. After 4 hours of incubation, no appreciable reduction of cell viability was seen for other doses in any of the cell lines. At 100 μM concentration, no significant loss of cell viability was seen in any of the cell lines when the incubation period was shortened to 30 minutes (p>0.05)[1].
In vitro, Zamicastat is a potent and selective dopamine β-hydroxylase inhibitor. It is a concentration-dependent dual inhibitor of P-gp and BCRP with IC₅₀ values of 73.8 μM and 17.0 μM, respectively. Its activity is assessed using enzyme inhibition assays measuring dopamine to norepinephrine conversion and transporter inhibition assays. |
| ln Vivo |
Acute testing of zamicastat (10, 30, and 100 mg/kg/day; oral bolus, 7 days) against salt-induced hypertension in Dahl SS rats was conducted. Blood pressure decreases in a dose-dependent manner when using zamicastat. Following zamicastat administration, the mean 24-hour systolic blood pressure (SBP) decreased by -12.6±4.1 mm Hg (P=0.0284), -15.2±2.7 mm Hg (P=0.0026), and -19.0±3.7 mm Hg (P =0.0036) for dosages of 10, 30, and 100 mg/kg body weight, respectively. A noteworthy decrease in diastolic blood pressure (DBP) of -14.6±3.4 mm Hg (P=0.0073) and -13.0±4.5 mm Hg at the 10 mg/kg body weight dose (P=0.0347) at the 30 mg/kg body weight dose and -15.0±3.1 mm Hg at the 100 mg/kg body weight dose (P=0.0046) was also observed upon zamicastat administration. The administration of zamicastat led to mean arterial pressure (MAP) decreases of -20.6±3.7 mm Hg at 24 hours post-dose, -14.0±3.5 mm Hg (P=0.0101), and -13.4±3.8 mm Hg (P=0.0162). (P=0.0026) at the doses of 10, 30, and 100 mg/kg body weight, in that order. For all tested dosages of zamicastat (10 mg/kg: -19.1±3.2 beats/min, P=0.0019; 30 mg/kg: -13.0±4.5 times/min, P=0.0347; 100 mg/kg: -21.6±6.6 times/min, P=0.0235), there was a slight but significant effect on mean heart rate (HR) 24 hours after dosing.
In vivo, Zamicastat increases levels of norepinephrine and decreases levels of dopamine in the hearts of aged spontaneously hypertensive rats (SHRs) when administered at a dose of 30 mg/kg per day. It prevents the deterioration of cardiometabolic and inflammatory biomarkers in a genetic model of salt-sensitive hypertension. It has antihypertensive effects. |
| Enzyme Assay |
In vitro enzyme inhibition assays for Zamicastat are performed using purified dopamine β-hydroxylase (DβH) enzyme. Enzyme activity is measured by quantifying the conversion of dopamine to norepinephrine using HPLC or radiometric methods. The compound is incubated with the enzyme and substrate, and the inhibition of DβH activity is quantified. Transporter inhibition is assessed using P-gp and BCRP assays.
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| Cell Assay |
Cell Viability Assay[1]
Cell Types: MDCK II, MDCK-MDR1 and MDCK-BCRP Cell Tested Concentrations: 5, 10, 20, 50, 80, 100 μM Incubation Duration: 4 hrs (hours) (5, 10, 20, 50, 80, 100 μM) or 30 minutes (100 μM only) Experimental Results: In MDCK-BCRP cells, 100 μM demonstrated a significant loss of cell viability. In vitro cellular assays for Zamicastat are performed using cells expressing DβH or transporter proteins. Cells are treated with the compound, and dopamine and norepinephrine levels are measured by HPLC. P-gp and BCRP transporter activity is assessed using fluorescent substrate accumulation assays. |
| Animal Protocol |
Animal/Disease Models: Sixweeks old male inbred male Dahl SS rat [2]
Doses: 10, 30 or 100 mg/kg; 4 mL/kg Route of Administration: Oral bolus, daily, 7 days Experimental Results: Treatment was dose-dependent Blood pressure drops. Twenty-four hrs (hrs (hours)) after administration, the mean systolic blood pressure decreases on days 10, 30, and 30 were -12.6±4.1 mmHg (P=0.0284), -15.2±2.7 mmHg (P=0.0026), and -19.0±3.7 mmHg. column (P=0.0036). and 100 mg/kg body weight dose respectively. Animal/Disease Models: Tenweeks old male Wistar Han rats [2] Doses: 30 mg/kg/day Route of Administration: Daily in animal feed (mixed into rodent food) Experimental Results: Caused significant levels of norepinephrine excretion in the body Dramatically diminished urine flow by 51% In vivo animal experiments for Zamicastat are conducted in spontaneously hypertensive rats (SHRs). A typical protocol involves administration of the compound (e.g., 30 mg/kg per day) to aged SHRs, followed by measurement of dopamine and norepinephrine levels in heart tissues. Blood pressure, cardiometabolic biomarkers, and inflammatory markers are also assessed. |
| ADME/Pharmacokinetics |
The pharmacokinetic properties of Zamicastat have been characterized in part. The compound has a molecular weight of 401.47 and molecular formula C₂₁H₂₁F₂N₃OS. It is a brain-penetrant compound that crosses the blood-brain barrier. It has a density of 1.4±0.1 g/cm³ and a boiling point of 525.8±60.0 °C. Further PK details are available from the manufacturer's data sheets.
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| Toxicity/Toxicokinetics |
Toxicological data for Zamicastat are available from preclinical studies supporting its development for hypertension and heart failure. As a DβH inhibitor and P-gp/BCRP inhibitor, its safety profile is characterized by its effects on catecholamine levels and drug transport. Specific toxicity data are available from regulatory submissions.
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| References |
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| Additional Infomation |
Zamicastat has been used in research trials for the treatment of hypertension and chronic heart failure.
Zamicastat is also known as BIA 5-1058. It is a dopamine β-hydroxylase inhibitor that crosses the blood-brain barrier and causes central and peripheral effects. It prevents the deterioration of cardiometabolic and inflammatory biomarkers in salt-sensitive hypertension. It has been investigated for hypertension and heart failure and was in Phase 1 clinical trials. This product is for research use only. |
| Molecular Formula |
C21H21F2N3OS
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| Molecular Weight |
401.4758
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| Exact Mass |
401.137
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| CAS # |
1080028-80-3
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| Related CAS # |
1080028-80-3;1383828-47-4 (HCl);
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| PubChem CID |
25052630
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| Appearance |
White to yellow solid powder
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| LogP |
4.349
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
5
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| Rotatable Bond Count |
6
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| Heavy Atom Count |
28
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| Complexity |
584
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| Defined Atom Stereocenter Count |
1
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| SMILES |
C1[C@H](COC2=C1C=C(C=C2F)F)N3C(=CNC3=S)CCNCC4=CC=CC=C4
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| InChi Key |
ZSSLCFLHEFXANG-GOSISDBHSA-N
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| InChi Code |
InChI=1S/C21H21F2N3OS/c22-16-8-15-9-18(13-27-20(15)19(23)10-16)26-17(12-25-21(26)28)6-7-24-11-14-4-2-1-3-5-14/h1-5,8,10,12,18,24H,6-7,9,11,13H2,(H,25,28)/t18-/m1/s1
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| Chemical Name |
4-[2-(benzylamino)ethyl]-3-[(3R)-6,8-difluoro-3,4-dihydro-2H-chromen-3-yl]-1H-imidazole-2-thione
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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 : ~150 mg/mL (~373.63 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (6.23 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 (6.23 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 (6.23 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 | 2.4908 mL | 12.4539 mL | 24.9078 mL | |
| 5 mM | 0.4982 mL | 2.4908 mL | 4.9816 mL | |
| 10 mM | 0.2491 mL | 1.2454 mL | 2.4908 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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