Zamicastat
Zamicastat Basic information
- Product Name:
- Zamicastat
- Synonyms:
-
- Zamicastat
- BIA 5-1058
- Zamicastat (BIA 5-1058)
- 2H-Imidazole-2-thione, 1-[(3R)-6,8-difluoro-3,4-dihydro-2H-1-benzopyran-3-yl]-1,3-dihydro-5-[2-[(phenylmethyl)amino]ethyl]-
- Zamicastat USP/EP/BP
- ABCB1,Dopamine β-monooxygenase,Inhibitor,Cluster of differentiation 243,ABCG2,inhibit,P-glycoprotein,Multidrug resistance protein 1,BCRP,MDR1,CD243,Breast cancer resistance protein,P-gp,Pgp,Zamicastat,Dopamine β-hydroxylase,Dopamine beta-hydroxylase,Dopamine beta-monooxygenase
- Zamicastat, 10 mM in DMSO
- 1-[6-[[(1S,3S)-3-aminocyclopentyl]amino]-3-pyridyl]pyridin-2-one dihydrochloride
- CAS:
- 1080028-80-3
- MF:
- C21H21F2N3OS
- MW:
- 401.47
- Mol File:
- 1080028-80-3.mol
Zamicastat Chemical Properties
- Boiling point:
- 525.8±60.0 °C(Predicted)
- Density
- 1.36±0.1 g/cm3(Predicted)
- storage temp.
- Store at -20°C
- solubility
- DMSO : 150 mg/mL (373.63 mM);Water : < 0.1 mg/mL (insoluble)
- form
- Solid
- pka
- 11.74±0.70(Predicted)
- color
- White to yellow
- InChIKey
- ZSSLCFLHEFXANG-GOSISDBHSA-N
- SMILES
- C1(=S)N([C@@H]2CC3=CC(F)=CC(F)=C3OC2)C(CCNCC2=CC=CC=C2)=CN1
Zamicastat Usage And Synthesis
Uses
Zamicastat (BIA 5-1058) is a dopamine β-hydroxylase (DBH) inhibitor and can cross the blood-brain barrier (BBB) to cause central as well as peripheral effects. Zamicastat is also a concentration-dependent dual P-gp and BCRP inhibitor with IC50 values of 73.8 μM and 17.0 μM, respectively[1]. Zamicastat reduces high blood pressure[2].
in vivo
Zamicastat (10, 30 and 100 mg/kg/day; oral bolus, 7 days) is tested acutely against salt-induced hypertension in the Dahl SS rat. Zamicastat produces a dose-dependent decrease in blood pressure. 24 h after Zamicastat administration mean systolic blood pressure (SBP) decrease is -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 the 10, 30, and 100 mg/kg body weight dose, respectively. Zamicastat administration also produces a significant 24-h average decrease in diastolic blood pressure (DBP) of - 14.6±3.4 mm Hg (P=0.0073) with 10 mg/kg body weight dose, -13.0±4.5 mm Hg (P=0.0347) with 30 mg/kg body weight dose and -15.0±3.1 mm Hg (P=0.0046) with 100 mg/kg body weight dose. Zamicastat administration leads to a decrease in the 24h post-dose mean arterial pressure (MAP) of -13.4±3.8 mm Hg (P=0.0162), -14.0±3.5 mm Hg (P=0.0101) and -20.6±3.7 mm Hg (P=0.0026) for the 10, 30, and 100 mg/kg body weight dose, respectively. There is a small, but significant, effect of Zamicastat on the 24-h mean heart rate (HR) post-dose for all tested doses (10 mg/kg: -19.1±3.2 beats/min, P=0.0019; 30 mg/kg: -13.0±4.5 beats/min, P=0.0347; 100 mg/kg: -21.6±6.6 beats/min, P=0.0235)[2].
| Animal Model: | Six-week-old male inbred male Dahl SS rats[2] |
| Dosage: | 10, 30, or 100 mg/kg; 4 mL/kg |
| Administration: | Oral bolus, daily, seven days |
| Result: | Treatment produced a dose-dependent decrease in blood pressure. Twenty four hours after administration mean SBP decrease was -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 the 10, 30, and 100 mg/kg body weight dose, respectively. |
| Animal Model: | ten-week-old male Wistar Han rats[2] |
| Dosage: | 30 mg/kg/day |
| Administration: | in animal feedings (mixed in meal rodent food) everyday |
| Result: | lead to a significant 51% decrease in noradrenaline levels excreted in urine |
References
[1] Bicker J, et al. In vitro assessment of the interactions of dopamine β-hydroxylase inhibitors with human P-glycoprotein and Breast Cancer Resistance Protein. Eur J Pharm Sci. 2018 May 30;117:35-40. DOI:10.1016/j.ejps.2018.02.006
[2] Igreja B, et al. Effects of Zamicastat treatment in a genetic model of salt-sensitive hypertension and heart failure. Eur J Pharmacol. 2019 Jan 5;842:125-132. DOI:10.1016/j.ejphar.2018.10.030
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