Nebicapone
(Synonyms: BIA 3-202) 目录号 : GC65175
Nebicapone (BIA 3-202) 是一种可逆的儿茶酚-O-甲基转移酶 (COMT) 抑制剂，主要通过葡萄糖醛酸化代谢。Nebicapone 主要是外周作用的抑制剂，通过抑制 COMT 降低 L-DOPA 向 3-O-甲基-DOPA 的生物转化，Nebicapone 可用于帕金森病的研究。
Cas No.:274925-86-9
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
- View current batch:
- Purity: >99.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
Nebicapone (BIA 3-202), a reversible catechol-O-methyltransferase (COMT) inhibitor, is mainly metabolized by glucuronidation. Nebicapone is mainly peripherally acting inhibitor that decreases the biotransformation of L-DOPA to 3-O-methyl-DOPA by inhibition of COMT, and it is potential for the treatment of Parkinson's disease[1].
[1]. Loureiro AI, et al. Human metabolism of nebicapone (BIA 3-202), a novel catechol-o-methyltransferase inhibitor: characterization of in vitro glucuronidation. Drug Metab Dispos. 2006 Nov;34(11):1856-62.
| Cas No. | 274925-86-9 | SDF | Download SDF |
| 别名 | BIA 3-202 | ||
| 分子式 | C14H11NO5 | 分子量 | 273.24 |
| 溶解度 | 储存条件 | 4°C, protect from light | |
| 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 | 3.6598 mL | 18.2989 mL | 36.5979 mL |
| 5 mM | 0.732 mL | 3.6598 mL | 7.3196 mL |
| 10 mM | 0.366 mL | 1.8299 mL | 3.6598 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 Nebicapone on the pharmacokinetics and pharmacodynamics of warfarin in healthy subjects
Eur J Clin Pharmacol 2008 Oct;64(10):961-6.PMID:18679669DOI:10.1007/s00228-008-0534-2.
Objective: Nebicapone is a new catechol-O-methyltransferase inhibitor. In vitro, Nebicapone has showed an inhibitory effect upon CYP2C9, which is responsible for the metabolism of S-warfarin. The objective of this study was to investigate the effect of Nebicapone on warfarin pharmacokinetics and pharmacodynamics in healthy subjects. Methods: Single-centre, open-label, randomised, two-period crossover study in 16 healthy volunteers. In one period, subjects received Nebicapone 200 mg thrice daily for 9 days and a racemic warfarin 25-mg single dose concomitantly with the Nebicapone morning dose on day 4 (test). In the other period, subjects received a racemic warfarin 25-mg single dose alone (reference). The treatment periods were separated by a washout of 14 days. Results: For R-warfarin, mean +/- SD C(max) was 1,619 +/- 284 ng/mL for test and 1,649 +/- 357 ng/mL for reference, while AUC(0-t ) was 92,796 +/- 18,976 ng x h/mL (test) and 73,597 +/- 11,363 ng x h/mL (reference). The R-warfarin test-to-reference geometric mean ratio (GMR) and 90% confidence interval (90%CI) were 0.973 (0.878-1.077) for C(max) and 1.247 (1.170-1.327) for AUC(0-t ). For S-warfarin, mean +/- SD C(max) was 1,644 +/- 331 ng/mL for test and 1,739 +/- 392 ng/mL for reference, while AUC(0-t ) was 66,627 +/- 41,199 ng x h/mL (test) and 70,178 +/- 42,560 ng x h/mL (reference). The S-warfarin test-to-reference GMR and 90%CI were 0.932 (0.845-1.028) for C(max) and 0.914 (0.875-0.954) for AUC(0-t ). No differences were found for the pharmacodynamic parameter (INR). Conclusion: Nebicapone showed no significant effect on S-warfarin pharmacokinetics or on the coagulation endpoint (INR). A mild inhibition of the R-warfarin metabolism was found but is unlikely to be of clinical relevance.
Chronopharmacology of Nebicapone, a new catechol-O-methyltransferase inhibitor
Curr Med Res Opin 2010 May;26(5):1097-108.PMID:20225994DOI:10.1185/03007991003694472.
Objective: To investigate the chronopharmacology of Nebicapone, a new catechol-O-methyltransferase (COMT) inhibitor currently being developed for use as an adjunct to levodopa/carbidopa or levodopa/benserazide in the treatment of Parkinson's disease. Methods: This was a double-blind, randomised, placebo-controlled, parallel-group study. Eighteen Caucasian subjects were randomly assigned to treatment with either Nebicapone 100 mg (n = 6), Nebicapone 200 mg (n = 6) or placebo (n = 6) at 4-h intervals for 7 days. First dose occurred at 8:00 AM on day 1 and last dose at 8:00 AM on day 8. Blood samples for the determination of plasma drug concentrations of Nebicapone and its glucuronidated and methylated metabolites and for the assay of erythrocyte soluble COMT (S-COMT) activity were taken at frequent times following the first and last doses, and before the 8:00 AM and 8:00 PM doses on days 2-7. Results: Three men and three women in each group participated in the study. Mean +/- SD (range) age of study participants was 23.7 +/- 3.1 (21-28) years in the Nebicapone 100 mg group, 22.2 +/- 0.4 (22-23) years in the Nebicapone 200 mg group and 24.3 +/- 5.4 (18-32) in the placebo group. A circadian variation in the pre-dose Nebicapone and nebicapone-glucuronide plasma concentrations was apparent. Both Nebicapone and nebicapone-glucuronide levels were lower before the 8 PM dose in comparison to the 8 AM dose, suggesting that the absorption of Nebicapone may follow a circadian variation. S-COMT activity showed no circadian variation in the placebo group. Therefore, the S-COMT activity variation found in nebicapone-treated subjects is considered to be due to changes in plasma concentrations of Nebicapone, which is consistent with the fact that the pre-dose S-COMT activity was lower at the time at which Nebicapone levels were maximal. Four subjects in the Nebicapone 100 mg and placebo groups and six subjects in the Nebicapone 200 mg group reported at least one adverse event (AE). All AEs were of mild or moderate intensity. Both Nebicapone treatment regimens were subjectively well-tolerated, but a clinically relevant elevation in aspartate transaminase was observed in one subject of each Nebicapone group. Conclusion: Nebicapone showed chronopharmacology in young Caucasian healthy subjects. The clinical impact of the circadian variation in the Nebicapone metabolism and activity in Parkinson's disease patients deserves evaluation as it may have implications for drug prescription by modulating the distribution of the total daily dose along the 24-h scale.
Effects of Nebicapone on levodopa pharmacokinetics, catechol-O-methyltransferase activity, and motor fluctuations in patients with Parkinson disease
Clin Neuropharmacol 2008 Jan-Feb;31(1):2-18.PMID:18303486DOI:10.1097/wnf.0b013e3180645cb0.
Objective: To investigate the effects of Nebicapone, a new catechol-O-methyltransferase (COMT) inhibitor, on levodopa pharmacokinetics, COMT activity, and motor fluctuations in Parkinson disease in comparison to placebo and entacapone. Methods: Randomized, double-blind, placebo-controlled, 4-way crossover study consisting of 4 treatment periods (6-9 days duration each) in 19 patients (65.3 +/- 8.5 years) treated with carbidopa/levodopa 3 to 7 times per day. Nebicapone/entacapone/placebo and carbidopa/levodopa doses were administered concomitantly. At the end of each period, a levodopa test was performed, and levodopa and 3-O-methyldopa levels and COMT activity were assayed. Results: After 75 mg Nebicapone, 150 mg Nebicapone, and 200 mg entacapone, levodopa area under the plasma concentration time curve significantly increased 28.1, 48.4, and 33.3%, and 3-O-methyldopa area under the plasma concentration time curve significantly decreased 59.2, 70.8, and 59.1%, respectively. Peak COMT inhibition was similar between active treatments, but extent of COMT inhibition was more sustained with 75 and 150 mg Nebicapone than with 200 mg entacapone. After the levodopa test doses, ON time significantly increased 29 minutes with 75 mg Nebicapone, 45 minutes with 150 mg Nebicapone, and 16 minutes with 200 mg entacapone. Patients' diaries showed a decrease in daily OFF time of 109 minutes with 75 mg Nebicapone, 103 minutes with 150 mg Nebicapone, and 71 minutes with 200 mg entacapone, and an increase in daily ON time of 74, 101, and 74 minutes, respectively. Treatments were generally well tolerated and safe; no relevant changes in liver function tests were reported. Conclusions: Nebicapone, a new COMT inhibitor, significantly decreased COMT activity, increased systemic exposure to levodopa, and improved motor response. Nebicapone deserves further evaluation in larger samples of patients.
Human metabolism of Nebicapone (BIA 3-202), a novel catechol-o-methyltransferase inhibitor: characterization of in vitro glucuronidation
Drug Metab Dispos 2006 Nov;34(11):1856-62.PMID:16790555DOI:10.1124/dmd.106.010447.
Nebicapone (BIA 3-202; 1-[3,4-dihydroxy-5-nitrophenyl]-2-phenylethanone), a novel catechol-O-methyltransferase inhibitor, is mainly metabolized by glucuronidation. The purpose of this study was to characterize the major plasma metabolites of Nebicapone following p.o. administration of Nebicapone to healthy volunteers, and to determine the human UDP-glucuronosyltransferase (UGT) enzymes involved in Nebicapone glucuronidation. Plasma samples were collected as part of a clinical trial at different time points postdose and were analyzed for Nebicapone and its metabolites using a validated method consisting of a solid-phase extraction, followed by high-performance liquid chromatography/mass spectrometry detection. The primary metabolic pathways of Nebicapone in humans involve mainly 3-O-glucuronidation, the major early metabolite, and 3-O-methylation, the predominant late metabolite. Of the nine commercially available recombinant UGT enzymes studied (UGT1A1, UGT1A3, UGT1A6, UGT1A7, UGT1A8, UGT1A9, UGT1A10, UGT2B7, and UGT2B15), only UGT1A9 exhibited high Nebicapone glucuronosyltransferase specific activity (24.3 +/- 1.3 nmol/mg protein/min). UGT1A6, UGT1A7, UGT1A8, UGT1A10, UGT2B7, and UGT2B15 exhibited low activity (0.1-1.1 nmol/mg protein/min), and UGT1A1 and UGT1A3 showed extremely low activities (less than 0.03 nmol/mg protein/min). The results show that Nebicapone is mainly glucuronidated in humans and that multiple UGT enzymes are involved in this reaction.
Species differences in pharmacokinetic and pharmacodynamic properties of Nebicapone
Biochem Pharmacol 2009 Oct 15;78(8):1043-51.PMID:19505437DOI:10.1016/j.bcp.2009.05.036.
The present study was designed to characterize pharmacodynamic and pharmacokinetic properties of Nebicapone in rats and mice. Upon oral administration of Nebicapone the extent of mouse liver catechol-O-methyltransferase (COMT) inhibition is half that in the rat. Nebicapone was rapidly absorbed reaching plasma C(max) within 30min and being completely eliminated by 8h. Nebicapone was metabolized mainly by glucuronidation and methylation in both species, but rat had an extra major metabolite, resulting from sulphation. Administration of Nebicapone by the intraperitoneal route significantly increased compound AUC in the rat while in the mouse a significant increase in AUC of metabolites was observed. These results show that Nebicapone exhibited marked species differences in bioavailability and metabolic profile. Evaluation of COMT activity in rat and mice liver homogenates revealed that both had similar methylation efficiencies (K(cat) values, respectively 7.3 and 6.4min(-1)), but rat had twice active enzyme units as the mouse (molar equivalency respectively 150 and 83). Furthermore, Nebicapone inhibited rat liver COMT with a lower K(i) than mouse liver COMT (respectively 0.2nM vs. 1.2nM). In conclusion, the results from the present study show that mice and rats respond differently to COMT inhibition by Nebicapone. The more pronounced inhibitory effects of Nebicapone in the rat may be related to an enhanced oral availability and less pronounced metabolism of Nebicapone in this specie, but also concerned with the predominant expression of S-COMT over MB-COMT, the latter of which is less sensitive to inhibition by Nebicapone than the former.