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Zamicastat (BIA 5-1058) Sale

(Synonyms: BIA 5-1058) 目录号 : GC32593

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) Chemical Structure

Cas No.:1080028-80-3

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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.

Chemical Properties

Cas No. 1080028-80-3 SDF
别名 BIA 5-1058
Canonical SMILES S=C1N([C@@H]2CC3=CC(F)=CC(F)=C3OC2)C(CCNCC4=CC=CC=C4)=CN1
分子式 C21H21F2N3OS 分子量 401.47
溶解度 DMSO : 150 mg/mL (373.63 mM);Water : < 0.1 mg/mL (insoluble) 储存条件 Store at -20°C
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储备液的保存方式和期限:-80°C 储存时,请在 6 个月内使用,-20°C 储存时,请在 1 个月内使用。
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1 mg 5 mg 10 mg
1 mM 2.4908 mL 12.4542 mL 24.9085 mL
5 mM 0.4982 mL 2.4908 mL 4.9817 mL
10 mM 0.2491 mL 1.2454 mL 2.4908 mL
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给药剂量 mg/kg 动物平均体重 g 每只动物给药体积 ul 动物数量
% DMSO % % Tween 80 % saline

Research Update

Effects of Zamicastat treatment in a genetic model of salt-sensitive hypertension and heart failure

Eur J Pharmacol 2019 Jan 5;842:125-132.PMID:30401628DOI:10.1016/j.ejphar.2018.10.030.

Hyperactivity of sympathetic nervous system plays an important role in the development and progression of cardiovascular diseases. An approach to mitigate the enhanced sympathetic nervous system drive is restricting the biosynthesis of noradrenaline via inhibition of the enzyme dopamine β-hydroxylase (DβH), that catalyzes the hydroxylation of dopamine to noradrenaline in sympathetic nerves. The aim of the present study was to evaluate the effects of Zamicastat, a novel DβH inhibitor that decreases noradrenaline and increases dopamine levels in peripheral sympathetically innervated tissues, on the hemodynamic and cardiometabolic parameters in salt-induced hypertension and heart failure in the Dahl salt-sensitive (SS) rat. Zamicastat (10, 30 and 100 mg/kg body weight) was tested acutely against salt-induced hypertension in the Dahl SS rat. Chronic Zamicastat treatment (30 mg/kg/day) was evaluated against salt-induced cardiac hypertrophy and biomarkers of cardiometabolic risk and inflammation in Dahl SS rats and upon the survival rate in aged Dahl SS rats fed a high-salt diet. The reduction in the sympathetic tone attained with Zamicastat shaped a dose- and time-dependent effect on blood pressure. Prolonged treatment with Zamicastat ameliorated end-organ damage, metabolic syndrome and inflammation hallmarks in hypertensive Dahl SS rats. Survival rate of Dahl SS rats fed a high-salt diet demonstrated that Zamicastat increased median survival of Dahl SS rats fed a high-salt diet. The use of DβH inhibitors, like Zamicastat, is a promising approach to treat hypertension, heart failure and cardiovascular diseases where a reduction in the sympathetic tone has beneficial effects.

Cardiometabolic and Inflammatory Benefits of Sympathetic Down-Regulation with Zamicastat in Aged Spontaneously Hypertensive Rats

ACS Pharmacol Transl Sci 2019 Sep 4;2(5):353-360.PMID:32259069DOI:10.1021/acsptsci.9b00039.

The hyperactivity of the sympathetic nervous system (SNS) plays a major role in the development and progression of several cardiovascular diseases. One strategy to mitigate the SNS overdrive is by restricting the biosynthesis of norepinephrine via the inhibition of dopamine β-hydroxylase (DBH). Zamicastat is a new DBH inhibitor that decreases norepinephrine and increases dopamine levels in peripherally sympathetic-innervated tissues. The cardiometabolic and inflammatory effects of sympathetic down-regulation were evaluated in 50 week old male spontaneously hypertensive rats (SHRs) receiving Zamicastat (30 mg/kg/day) for 9 weeks. After 8 weeks of treatment, the blood pressure (BP) and heart rate (HR) were assessed by tail cuff plethysmography. At the end of the study, 24 h urine, plasma, heart, and kidney were collected for biochemical and morphometric analyses. Zamicastat-induced sympathetic down-regulation decreased the high BP in SHRs, with no observed effect on HR. The heart-to-body weight ratio was lower in SHRs treated with Zamicastat, whereas the body weight and kidney-to-body weight ratio were similar between both SHR cohorts. Zamicastat-treated SHRs showed reduced 24 h urine output, but the urinary amount of protein excreted and creatinine clearance rate remained unchanged. Zamicastat treatment significantly decreased plasma triglycerides, free fatty acids, and aspartate aminotransferase levels. Aged SHRs showed higher plasma levels of inflammatory markers as compared with age-matched normotensive Wistar-Kyoto rats. The inflammatory benefits attained with DBH inhibition were expressed by a decrease in CRP, MCP-1, IL-5, IL-17α, GRO/KC, MIP-1α, and RANTES plasma levels as compared with untreated SHRs. In conclusion, DBH inhibition decreased norepinephrine levels, reduced end-organ damage, and improved cardiometabolic and inflammatory biomarkers in aged male SHRs.

Dopamine β hydroxylase as a potential drug target to combat hypertension

Expert Opin Investig Drugs 2020 Sep;29(9):1043-1057.PMID:32658551DOI:10.1080/13543784.2020.1795830.

Introduction: Despite a large number of commercially available drugs, hypertension and related cardiovascular diseases remain a global problem. It is thus imperative that novel drugs and therapeutic strategies are regularly identified, and alternative targets explored. Dopamine β hydroxylase (DBH), a key player in the catecholamine biosynthetic pathway, may provide a therapeutic opportunity and should be extensively explored as a target for potent anti-hypertensives. Inhibitors of DBH have been successful in combating hypertension, as evidenced by the outcome of clinical trials for etamicastat and Zamicastat. Areas covered: We shed light on the strategies employed to identify inhibitors of the enzyme and outline the advantages that the target might offer. Structural and functional details of the enzyme are described along with specific methodologies for drug discovery that were never utilized for the therapeutic target. Expert opinion: Effective inhibitors of the enzyme may be identified with computer-aided structure-based design. Adoption of new methodologies and the assessment of newly designed inhibitors in DBH-specific animal models will provide new, safe, and cost-effective therapeutic opportunities.

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.PMID:29428540DOI:10.1016/j.ejps.2018.02.006.

Inhibition of the biosynthesis of noradrenaline is a currently explored strategy for the treatment of hypertension, congestive heart failure and pulmonary arterial hypertension. While some dopamine β-hydroxylase (DBH) inhibitors cross the blood-brain barrier (BBB) and cause central as well as peripheral effects (nepicastat), others have limited access to the brain (etamicastat, Zamicastat). In this context, peripheral selectivity is clinically advantageous, in order to prevent alterations of noradrenaline levels in the CNS and the occurrence of adverse central effects. A limited brain exposure results from the combination of several factors, such as a reduced passive permeability or affinity for efflux transporters, but efflux liabilities may also lead to unwanted drug-drug interactions (DDIs) in the presence of co-administered substrates or inhibitors. Thus, the purpose of the study herein presented was to explore the interaction of P-glycoprotein (P-gp) and Breast Cancer Resistance Protein (BCRP), the two major efflux transporters of the BBB that hamper the entry of several drugs to the brain, with the DBH inhibitors, etamicastat, nepicastat and Zamicastat. Madin-Darby canine kidney cells (MDCK II) and transfected lines with human MDR1 (MDCK-MDR1) and ABCG2 (MDCK-BCRP) genes were used as a BBB surrogate model. P-gp and BCRP substrates and/or inhibitors were identified through intracellular accumulation and bidirectional permeability assays. The obtained data revealed that Zamicastat is a concentration-dependent dual P-gp and BCRP inhibitor with IC50 values of 73.8 ± 7.2 μM and 17.0 ± 2.7 μM, while etamicastat and nepicastat inhibited BCRP to greater extent than P-gp, with IC50 values of 47.7 ± 1.8 μM and 59.2 ± 9.4 μM, respectively. Additionally, etamicastat was identified as P-gp and BCRP dual substrate, as demonstrated by net flux ratios of 5.84 and 3.87 and decreased >50% by verapamil and Ko143. Conversely, nepicastat revealed to be a P-gp-only substrate, with a net flux ratio of 2.01, reduced to 0.92 in the presence of verapamil. Furthermore, nepicastat displayed a consistently higher apparent permeability (>8.49 × 10-6 cm s-1) than etamicastat (<0.58 × 10-6 cm s-1). The identification of etamicastat as a dual efflux substrate suggests that P-gp and BCRP may be partially responsible for the limited central exposure of this compound, in association with its low passive permeability. Moreover, the weak efflux inhibitory potencies of etamicastat and nepicastat revealed a low DDI risk, while the dual P-gp/BCRP inhibition of Zamicastat could be studied in the future with synergically effluxed compounds, for which BBB penetration is severely impaired.