Zamicastat (BIA 5-1058) (BIA 5-1058) 是一种多巴胺 β-羟化酶 (DBH) 抑制剂，可穿过血脑屏障 (BBB) 引起中枢和外周效应。
Zamicastat (BIA 5-1058) is a dopamine β-hydroxylase (DBH) inhibitor that could cross the blood-brain barrier (BBB) and 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]. Reduces high blood pressure[2].
Following 4 hours of incubation (5, 10, 20, 50, 80, 100 μM), a significant loss of cell viability is verified with 100 μM Zamicastat (p=0.010) in MDCK-BCRP cells. No significant losses of cell viability are observed after 4 h of incubation for other concentrations in all cell lines. By decreasing the incubation period to 30 min, there is no significant loss of cell viability (p>0.05) at 100 μM in all cell lines[1].|| Cell Viability Assay[1]||Cell Line:|MDCK II, MDCK-MDR1 and MDCK-BCRP cells|Concentration:|5, 10, 20, 50, 80, 100 μμ|Incubation Time:|4 hours (5, 10, 20, 50, 80, 100 μM) or 30 min (only 100 μM)|Result:|A significant loss of cell viability was verified with 100 μM in MDCK-BCRP cells.
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
[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. [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.
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