Zamicastat (BIA 5-1058)
目录号 : GC32593
Sample solution is provided at 25 µL, 10mM.
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| 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 |
| General tips | For obtaining a higher solubility , please warm the tube at 37 ℃ and shake it in the ultrasonic bath for a while. | ||
| Shipping Condition | Evaluation sample solution : ship with blue ice All other available size: ship with RT , or blue ice upon request |
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| 制备储备液 | |||
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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 |
| 第一步：请输入基本实验信息（考虑到实验过程中的损耗，建议多配一只动物的药量） | ||||||||||
| 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 | 只 |
| 第二步：请输入动物体内配方组成（配方适用于不溶于水的药物；不同批次药物配方比例不同，请联系GLPBIO为您提供正确的澄清溶液配方） | ||||||||||
| % DMSO % % Tween 80 % saline | ||||||||||
| 计算重置 | ||||||||||
计算结果:
工作液浓度： mg/ml；
DMSO母液配制方法： mg 药物溶于 μL DMSO溶液（母液浓度 mg/mL，
体内配方配制方法：取 μL DMSO母液，加入 μL PEG300，混匀澄清后加入μL Tween 80，混匀澄清后加入 μL saline，混匀澄清。
1. 首先保证母液是澄清的；
2.
一定要按照顺序依次将溶剂加入，进行下一步操作之前必须保证上一步操作得到的是澄清的溶液，可采用涡旋、超声或水浴加热等物理方法助溶。
3. 以上所有助溶剂都可在 GlpBio 网站选购。
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.