Etamicastat (BIA 5-453)
(Synonyms: (R)-5-(2-氨基乙基)-1-(6,8-二氟苯并二氢吡喃-3-基)-1,3-二氢咪唑-2-硫酮,BIA 5-453) 目录号 : GC32575
Etamicastat (BIA 5-453) (BIA 5-453) 是一种有效且可逆的多巴胺-β-羟化酶 (DBH) 抑制剂，IC50 值为 107 nM。
Cas No.:760173-05-5
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
- View current batch:
- Purity: >98.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
Etamicastat (BIA 5-453) is a potent and reversible peripheral dopamine-β-hydroxylase (DβH) inhibitor[1].
Upon intraperitoneal administration to NMRi mice, Etamicastat (100 mg/ kg) leads to a significant reduction of noradrenaline levels (36% control) in heart with concomitant increasing in dopamine levels (850% of control)[2].Etamicastat (50 mg/kg) is rapidly absorbed into the systemic circulation reaching a maximum concentration at 4 h post-administration, representing 29% of total Etamicastat and quantified metabolites, using AUC0-t as a measure of systemic exposure[2].
[1]. Vaz-da-Silva M, et al. Effect of food on the pharmacokinetic profile of Etamicastat (BIA 5-453). Drugs R D. 2011;11(2):127-36. [2]. Loureiro AI, et al. Etamicastat, a new dopamine-?-hydroxylase inhibitor, pharmacodynamics and metabolism in rat. Eur J Pharmacol. 2014 Oct 5;740:285-94.
| Cas No. | 760173-05-5 | SDF | |
| 别名 | (R)-5-(2-氨基乙基)-1-(6,8-二氟苯并二氢吡喃-3-基)-1,3-二氢咪唑-2-硫酮,BIA 5-453 | ||
| Canonical SMILES | S=C1NC=C(CCN)N1[C@H]2COC3=C(C=C(F)C=C3F)C2 | ||
| 分子式 | C14H15F2N3OS | 分子量 | 311.35 |
| 溶解度 | Soluble in DMSO | 储存条件 | Store at -20°C |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 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。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
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| Shipping Condition | 评估样品解决方案：配备蓝冰进行发货。所有其他可用尺寸：配备RT，或根据请求配备蓝冰。 | ||
| 制备储备液 | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 3.2118 mL | 16.0591 mL | 32.1182 mL |
| 5 mM | 0.6424 mL | 3.2118 mL | 6.4236 mL |
| 10 mM | 0.3212 mL | 1.6059 mL | 3.2118 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。
Effect of food on the pharmacokinetic profile of Etamicastat (BIA 5-453)
Drugs R D 2011;11(2):127-36.PMID:21548660DOI:10.2165/11587080-000000000-00000.
Background: Etamicastat is a novel, potent, and reversible peripheral dopamine-β-hydroxylase inhibitor that has been administered orally at doses up to 600 mg once daily for 10 days to male healthy volunteers and appears to be well tolerated. Objective: The aim of this study was to investigate the effect of food on the pharmacokinetics of etamicastat. Material and methods: A single-center, open-label, randomized, two-way crossover study in 12 healthy male subjects was performed. Subjects were administered a single dose of etamicastat 200 mg following either a standard high-fat and high-calorie content meal (test) or 10 hours of fasting (reference). The statistical method for testing the effect of food on the pharmacokinetic parameters of interest was based upon the 90% confidence interval (CI) for the test/reference geometric mean ratio (GMR). The parameters of interest were maximum plasma concentration (C(max)), area under the plasma concentration-time curve (AUC) from time zero to the last measurable concentration (AUC(last)), and AUC from time zero to infinity (AUC(∞)). Bioequivalence was assumed when the 90% CI fell within the recommended acceptance interval (80, 125). Results: Etamicastat C(max), AUC(last), and AUC(∞) were 229 ng/mL, 1856 ng · h/mL, and 2238 ng · h/mL, respectively, following etamicastat in the fasting, and 166 ng/mL, 1737 ng · h/mL, and 2119 ng · h/mL, respectively, following etamicastat in the fed condition. Etamicastat test/reference GMR was 72.27% (90% CI 64.98, 80.38) for C(max), 93.59% (90% CI 89.28, 98.11) for AUC(last), and 96.47% (90% CI 91.67, 101.53) for AUC(∞). Time to C(max) was prolonged by the presence of food (p < 0.001). The C(max), AUC(last), and AUC(∞) values of the inactive metabolite BIA 5-961 were 275 ng/mL, 1827 ng · h/mL, and 2009 ng · h/mL, respectively, in the fasting, and 172 ng/mL, 1450 ng · h/mL, and 1677 ng · h/mL, respectively, in the fed condition. BIA 5-961 test/reference GMR was 62.42% (90% CI 56.77, 68.63) for C(max), 79.41% (90% CI 56.77, 68.63) for AUC(last), and 83.47% (90% CI 76.62, 90.93) for AUC(∞). A total of six mild to moderate unspecific adverse events were reported by four subjects. There was no clinically significant abnormality in laboratory assessments. Conclusion: Etamicastat was well tolerated. The C(max) of etamicastat decreased 28% following oral administration of etamicastat in the presence of food, while AUC remained within the pre-defined acceptance interval. The delay in absorption and decrease in peak exposure of etamicastat is not clinically significant, and therefore etamicastat could be administered without regard to meals. Trial registration: EudraCT No. 2007-006530-33.
Distribution and pharmacokinetics of Etamicastat and its N-acetylated metabolite (BIA 5-961) in dog and monkey
Xenobiotica 2015;45(10):903-11.PMID:25869244DOI:10.3109/00498254.2015.1024780.
1. The disposition Etamicastat was evaluated in the Cynomolgus monkey after intravenous and oral administration of [(14)C]-etamicastat. The pharmacokinetics of Etamicastat and its N-acetylated metabolite BIA 5-961 were also evaluated in monkeys and dogs. 2. In the monkey, 7 days after intravenous and oral administration of [(14)C]-etamicastat, 76.6-91.1% of the etamicastat-related radioactivity had been excreted mainly in urine. The radioactivity peaked in plasma between 4- and 8-h post-dosing followed by a quick decline and a slow terminal phase (half-life of 68.7 h). The calculated oral bioavailability for Etamicastat was 46.1%. Etamicastat was quickly absorbed in monkeys and dogs with a half-life ranging from 5.2 to 9.9 h in monkeys and 6.9 to 11.4 h in dogs over. 3. The N-acetylated metabolite of Etamicastat, represented 4-7% of the extent of exposure of Etamicastat in the monkey, but was not found detectable in dogs. Gender did not influence Etamicastat exposure and the concentration versus time curves fitted a dose-dependent pharmacokinetics in the dog, but not in the monkey. 4. In conclusion, Etamicastat is rapidly absorbed and primarily excreted via urine in monkeys. Similarly, to humans, monkeys, unlike dogs, N-acetylate Etamicastat and evidence that Etamicastat pharmacokinetics is less than dose proportional.
Single-dose tolerability, pharmacokinetics, and pharmacodynamics of Etamicastat (BIA 5-453), a new dopamine β-hydroxylase inhibitor, in healthy subjects
J Clin Pharmacol 2012 Feb;52(2):156-70.PMID:21343348DOI:10.1177/0091270010390805.
The safety, tolerability, pharmacokinetics, and pharmacodynamics of Etamicastat (BIA 5-453), a novel dopamine β-hydroxylase (DβH) inhibitor, were investigated in 10 sequential groups of 8 healthy male subjects under a double-blind, randomized, placebo-controlled design. In each group, 6 subjects received a single dose of etamicastat (2, 10, 20, 50, 100, 200, 400, 600, 900, or 1200 mg) and 2 subjects received placebo. Etamicastat was well tolerated at all dose levels tested. Maximum plasma etamicastat concentrations occurred at 1 to 3 hours postdose. Elimination was biphasic, characterized by a first short early elimination half-life followed by a longer elimination phase of 16 to 20 hours for etamicastat doses of 100 mg and above. A high interindividual variability of pharmacokinetic parameters of etamicastat and its acetylated metabolite was observed. Pharmacogenomic data showed that N-acetyltransferase type 2 (NAT2) phenotype (rapid or slow N-acetylating ability) was a major source of variability. In NAT2 poor acetylators, the area under the plasma concentration-time curve from time zero to the last sampling time at which concentrations were at or above the limit of quantification (AUC0-t ) of etamicastat was twice that observed in rapid acetylators. Consistent with that finding, AUC0-t of the acetylated metabolite was markedly higher in NAT2 rapid acetylators compared with poor acetylators. Inhibition of DβH activity was observed, reaching statistical significance for etamicastat doses of 100 mg and above.
Etamicastat, a new dopamine-ß-hydroxylase inhibitor, pharmacodynamics and metabolism in rat
Eur J Pharmacol 2014 Oct 5;740:285-94.PMID:25058908DOI:10.1016/j.ejphar.2014.07.027.
Despite the importance of sympathetic nervous system in pathophysiological mechanisms of cardiac heart failure and essential hypertension, therapy specifically targeting the sympathetic nervous system is currently underutilized. Etamicastat is a novel dopamine-ß-hydroxylase (DBH) inhibitor that is oxidized into BIA 5-965 and deaminated followed by oxidation to BIA 5-998, which represents 13% of total Etamicastat and quantified metabolites. However, the primary metabolic pathway of Etamicastat in rats was found to be the N-acetylation (BIA 5-961), which represents 44% of total Etamicastat and quantified metabolites. Trace amounts of BIA 5-961 de-sulfated and S-glucuronide were also detected. All the main metabolites of Etamicastat inhibited DBH with IC50 values of 306 (228, 409), 629 (534, 741), 427 (350, 522) nM for BIA 5-965, BIA 5-998 and BIA 5-961, respectively. However, only Etamicastat (IC50 of 107 (94; 121) nM) was able to reduce catecholamine levels in sympathetic nervous system innervated peripheral tissues, without effect upon brain catecholamines. Quantitative whole body autoradiography revealed a limited transfer of Etamicastat related radioactivity to brain tissues and the mean recovery of radioactivity was ~90% of the administered radioactive dose, eliminated primarily via renal excretion over 5 days. The absolute oral bioavailability of Etamicastat was 64% of the administered dose. In conclusion, Etamicastat is a peripheral selective DBH inhibitor mainly N-acetylated in the aminoethyl moiety and excreted in urine. Etamicastat main metabolites inhibit DBH, but only Etamicastat demonstrated unequivocal pharmacological effects as a DBH inhibitor with impact upon the activity of the sympathetic nervous system under in vivo conditions.
Human disposition, metabolism and excretion of Etamicastat, a reversible, peripherally selective dopamine β-hydroxylase inhibitor
Br J Clin Pharmacol 2014 Jun;77(6):1017-26.PMID:24168152DOI:10.1111/bcp.12274.
Aims: Etamicastat is a reversible dopamine-β-hydroxylase inhibitor that decreases noradrenaline levels in sympathetically innervated tissues and slows down sympathetic nervous system drive. In this study, the disposition, metabolism and excretion of Etamicastat were evaluated following [(14)C]-etamicastat dosing. Methods: Healthy Caucasian males (n = 4) were enrolled in this single-dose, open-label study. Subjects were administered 600 mg of unlabelled Etamicastat and 98 µCi weighing 0.623 mg [(14)C]-etamicastat. Blood samples, urine and faeces were collected to characterize the disposition, excretion and metabolites of Etamicastat. Results: Eleven days after administration, 94.0% of the administered radioactivity had been excreted; 33.3 and 58.5% of the administered dose was found in the faeces and urine, respectively. Renal excretion of unchanged Etamicastat and its N-acetylated metabolite (BIA 5-961) accounted for 20.0 and 10.7% of the dose, respectively. Etamicastat and BIA 5-961 accounted for most of the circulating radioactivity, with a BIA 5-961/Etamicastat ratio that was highly variable both for the maximal plasma concentration (19.68-226.28%) and for the area under the plasma concentration-time curve from time zero to the last sampling time at which the concentration was above the limit of quantification (15.82- 281.71%). Alongside N-acetylation, metabolism of Etamicastat also occurs through oxidative deamination of the aminoethyl moiety, alkyl oxidation, desulfation and glucuronidation. Conclusions: Etamicastat is rapidly absorbed, primarily excreted via urine, and its biotransformation occurs mainly via N-acetylation (N-acetyltransferase type 2), although glucuronidation, oxidation, oxidative deamination and desulfation also take place.