Sapropterin dihydrochloride (6R-BH4 dihydrochloride)
(Synonyms: 盐酸沙丙蝶呤; (6R)-BH4 dihydrochloride; (6R)-Tetrahydro-L-biopterin dihydrochloride) 目录号 : GC32438
A cofactor for production of aromatic amino acids, neurotransmitters, and nitric oxide
Cas No.:69056-38-8
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
- View current batch:
- Purity: >99.50%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
(6R)-5,6,7,8-tetrahydro-L-Biopterin (hydrochloride) (BH4) is a cofactor that, in the presence of enzyme site iron, binds to phenylalanine hydroxylase, tryptophan or tyrosine hydroxylase, and nitric oxide synthase (NOS), to facilitate the production of aromatic amino acids, neurotransmitters, and nitric oxide (NO), respectively.1,2,3 It is formed de novo from GTP with GTP cyclohydrolase-1 (GCH1) catalyzing the rate limiting conversion of GTP to 7,8-dihydroneopterin (NH2TP) followed by subsequent processing by TS and SPR to convert NH2TP to BH4.4,3 BH4 acts as a radical-trapping antioxidant that inhibits phospholipid oxidation in lipid membranes.4 It inhibits IKE- or RSL3-induced ferroptosis in HT-1080 cells (EC50s = 21 and 69 ?M), as well as ferroptosis induced by knockout of glutathione peroxidase (Gpx4-/-) in immortalized mouse fibroblasts.3 BH4 also reduces RLS3-induced lipid peroxidation in murine fibroblasts and HT-1080 cells when used at a concentration of 50 ?M.
1.Kappock, T.J., and Caradonna, J.P.Pterin-dependent amino acid hydroxylasesChem. Rev.96(7)2659-2756(1996) 2.Mayer, B., and Werner, E.R.In search of a function for tetrahydrobiopterin in the biosynthesis of nitric oxideN.-S. Arch. Pharmacol.351(5)453-463(1995) 3.Kraft, V.A.N., Bezjian, C.T., Pfeiffer, S., et al.GTP cyclohydrolase 1/tetrahydrobiopterin counteract ferroptosis through lipid remodelingACS Cent. Sci.6(1)41-53(2020) 4.Soula, M., Weber, R.A., Zilka, O., et al.Metabolic determinants of cancer cell sensitivity to canonical ferroptosis inducersNat. Chem. Biol.16(12)1351-1360(2020)
| Cas No. | 69056-38-8 | SDF | |
| 别名 | 盐酸沙丙蝶呤; (6R)-BH4 dihydrochloride; (6R)-Tetrahydro-L-biopterin dihydrochloride | ||
| Canonical SMILES | O=C1N=C(N)NC2=C1N[C@@H]([C@@H](O)[C@@H](O)C)CN2.[H]Cl.[H]Cl | ||
| 分子式 | C9H17Cl2N5O3 | 分子量 | 314.17 |
| 溶解度 | DMSO : 63mg/mL, Water : 34 mg/mL | 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 | 3.183 mL | 15.915 mL | 31.8299 mL |
| 5 mM | 0.6366 mL | 3.183 mL | 6.366 mL |
| 10 mM | 0.3183 mL | 1.5915 mL | 3.183 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。
Sapropterin dihydrochloride for phenylketonuria
Cochrane Database Syst Rev 2015 Mar 27;2015(3):CD008005.PMID:25812600DOI:10.1002/14651858.CD008005.pub4.
Background: Phenylketonuria results from a deficiency of the enzyme phenylalanine hydroxylase. Dietary restriction of phenylalanine keeps blood phenylalanine concentration low. Most natural foods are excluded from diet and supplements are used to supply other nutrients. Recent publications report a decrease in blood phenylalanine concentration in some patients treated with Sapropterin dihydrochloride. We examined the evidence for the use of Sapropterin dihydrochloride to treat phenylketonuria. This is an update of a previously published Cochrane Review. Objectives: To assess the safety and efficacy of Sapropterin dihydrochloride in lowering blood phenylalanine concentration in people with phenylketonuria. Search methods: We identified relevant trials from the Group's Inborn Errors of Metabolism Trials Register. Date of last search: 11 August 2014.We also searched ClinicalTrials.gov and Current controlled trials. Last search: 4 September 2014We contacted the manufacturers of the drug (BioMarin Pharmaceutical Inc.) for information regarding any unpublished trials. Selection criteria: Randomized controlled trials comparing sapropterin with no supplementation or placebo in people with phenylketonuria due to phenylalanine hydroxylase deficiency. Data collection and analysis: Two authors independently assessed trials and extracted outcome data. Main results: Two placebo-controlled trials were included. One trial administered 10 mg/kg/day sapropterin in 89 children and adults with phenylketonuria whose diets were not restricted and who had previously responded to saproterin.This trial measured change in blood phenylalanine concentration. The second trial screened 90 children (4 to 12 years) with phenylketonuria whose diet was restricted, for responsiveness to sapropterin. Forty-six responders entered the placebo-controlled part of the trial and received 20 mg/kg/day sapropterin. This trial measured change in both phenylalanine concentration and protein tolerance. Both trials reported adverse events. The trials showed an overall low risk of bias; but both are Biomarin-sponsored. One trial showed a significant lowering in blood phenylalanine concentration in the sapropterin group (10 mg/kg/day), mean difference -238.80 渭mol/L (95% confidence interval -343.09 to -134.51); a second trial (20 mg/kg/day sapropterin) showed a non-significant difference, mean difference -51.90 渭mol/L (95% confidence interval -197.27 to 93.47). The second trial also reported a significant increase in phenylalanine tolerance, mean difference18.00 mg/kg/day (95% confidence interval 12.28 to 23.72) in the 20 mg/kg/day sapropterin group. Authors' conclusions: There is evidence of short-term benefit from using sapropterin in some people with sapropterin-responsive forms of phenylketonuria; blood phenylalanine concentration is lowered and protein tolerance increased. There are no serious adverse events associated with using sapropterin in the short term.There is no evidence on the long-term effects of sapropterin and no clear evidence of effectiveness in severe phenylketonuria.
Sapropterin dihydrochloride for phenylketonuria
Cochrane Database Syst Rev 2012 Dec 12;12:CD008005.PMID:23235653DOI:10.1002/14651858.CD008005.pub3.
Background: Phenylketonuria results from a deficiency of the enzyme phenylalanine hydroxylase. Dietary restriction of phenylalanine keeps blood phenylalanine concentration low. Most natural foods are excluded from diet and supplements are used to supply other nutrients. Recent publications report a decrease in blood phenylalanine concentration in some patients treated with Sapropterin dihydrochloride. We examined the evidence for the use of Sapropterin dihydrochloride to treat phenylketonuria. Objectives: To assess the safety and efficacy of Sapropterin dihydrochloride in lowering blood phenylalanine concentration in people with phenylketonuria. Search methods: We identified relevant trials from the Group's Inborn Errors of Metabolism Trials Register. Date of last search: 29 June 2012.We also searched ClinicalTrials.gov and Current controlled trials. Last search: 23 July 2012.We contacted the manufacturers of the drug (BioMarin Pharmaceutical Inc.) for information regarding any unpublished trials. Selection criteria: Randomized controlled trials comparing sapropterin with no supplementation or placebo in people with phenylketonuria due to phenylalanine hydroxylase deficiency. Data collection and analysis: Two authors independently assessed trials and extracted outcome data. Main results: Two placebo-controlled trials were included. One trial administered 10 mg/kg/day sapropterin in 89 children and adults with phenylketonuria whose diets were not restricted and who had previously responded to saproterin.This trial measured change in blood phenylalanine concentration. The second trial screened 90 children (4 to 12 years) with phenylketonuria whose diet was restricted, for responsiveness to sapropterin. Forty-six responders entered the placebo-controlled part of the trial and received 20 mg/kg/day sapropterin. This trial measured change in both phenylalanine concentration and protein tolerance. Both trials reported adverse events. The trials showed an overall low risk of bias; but both are Biomarin-sponsored. One trial showed a significant lowering in blood phenylalanine concentration in the sapropterin group (10 mg/kg/day), mean difference -238.80 渭mol/L (95% confidence interval -343.09 to -134.51); a second trial (20 mg/kg/day sapropterin) showed a non-significant difference, mean difference -51.90 渭mol/L (95% confidence interval -197.27 to 93.47). The second trial also reported a significant increase in phenylalanine tolerance, mean difference18.00 mg/kg/day (95% confidence interval 12.28 to 23.72) in the 20 mg/kg/day sapropterin group. Authors' conclusions: There is evidence of short-term benefit from using sapropterin in some patients with sapropterin-responsive forms of phenylketonuria; blood phenylalanine concentration is lowered and protein tolerance increased. There are no serious adverse events associated with using sapropterin in the short term.There is no evidence on the long-term effects of sapropterin and no clear evidence of effectiveness in severe phenylketonuria.
Sapropterin dihydrochloride for phenylketonuria
Cochrane Database Syst Rev 2010 Jun 16;(6):CD008005.PMID:20556789DOI:10.1002/14651858.CD008005.pub2.
Background: Phenylketonuria results from a deficiency of the enzyme phenylalanine hydroxylase. Dietary restriction of phenylalanine keeps blood phenylalanine concentration low. Most natural foods are excluded from diet and supplements are used to supply other nutrients. Recent publications report a decrease in blood phenylalanine concentration in some patients treated with Sapropterin dihydrochloride. We examined the evidence for the use of Sapropterin dihydrochloride to treat phenylketonuria. Objectives: To assess the safety and efficacy of Sapropterin dihydrochloride in lowering blood phenylalanine concentration in people with phenylketonuria. Search strategy: We identified relevant trials from the Group's Inborn Errors of Metabolism Trials Register. Last search:07 May 2010.We also searched ClinicalTrials.gov and Current controlled trials. Last search: 01 September 2009.We contacted the manufacturers of the drug (BioMarin Pharmaceutical Inc.) for information regarding any unpublished trials. Selection criteria: Randomized controlled trials comparing sapropterin with no supplementation or placebo in people with phenylketonuria due to phenylalanine hydroxylase deficiency. Data collection and analysis: Two authors independently assessed trials and extracted outcome data. Main results: Two placebo-controlled trials were included. One trial administered 10 mg/kg/day sapropterin in 89 children and adults with phenylketonuria whose diets were not restricted and who had previously responded to saproterin.This trial measured change in blood phenylalanine concentration. The second trial screened 90 children (4 to 12 years) with phenylketonuria whose diet was restricted, for responsiveness to sapropterin. Forty-six responders entered the placebo-controlled part of the trial and received 20 mg/kg/day sapropterin. This trial measured change in both phenylalanine concentration and protein tolerance. Both trials reported adverse events. The trials showed an overall low risk of bias; but both are Biomarin-sponsored. One trial showed a significant lowering in blood phenylalanine concentration in the sapropterin group (10 mg/kg/day), mean difference -238.80 mumol/L (95% confidence interval -343.09 to -134.51); a second trial (20 mg/kg/day sapropterin) showed a non-significant difference, mean difference -51.90 mumol/L (95% confidence interval -197.27 to 93.47). The second trial also reported a significant increase in phenylalanine tolerance, mean difference18.00 mg/kg/day (95% confidence interval 12.28 to 23.72) in the 20 mg/kg/day sapropterin group. Authors' conclusions: There is evidence of short-term benefit from using sapropterin in some patients with sapropterin-responsive forms of phenylketonuria; blood phenylalanine concentration is lowered and protein tolerance increased. There are no serious adverse events associated with using sapropterin in the short term.There is no evidence on the long-term effects of sapropterin and no clear evidence of effectiveness in severe phenylketonuria.
Sapropterin dihydrochloride for the treatment of hyperphenylalaninemias
Expert Opin Drug Metab Toxicol 2013 Sep;9(9):1207-18.PMID:23705856DOI:10.1517/17425255.2013.804064.
Introduction: Phenylketonuria (PKU) is caused by mutation of the enzyme, phenylalanine (Phe) hydroxylase (PAH). The hyperphenylalaninemia characteristic of PKU causes devastating neurological damage if not identified and treated at birth with a Phe-restricted diet. Sapropterin dihydrochloride, a pharmaceutical formulation of the natural cofactor for PAH (6R-tetrahydrobiopterin; BH4), is now available for the management of hyperphenylalaninemia in some PKU patients, including BH4 deficiencies. Sapropterin dihydrochloride improves dietary Phe tolerance in about 20% of patients with PKU. Areas covered: This evaluation describes the identification of patients suitable for treatment of Sapropterin dihydrochloride, together with its indications, therapeutic properties and efficacy. Furthermore, the article reviews its safety and tolerability in patients with PKU or BH4 deficiency. Expert opinion: A reduction in blood Phe of at least 30% occurred in 鈭?20 - 30% of sapropterin-treated PKU patients (mostly with milder forms of PKU). Treatment with sapropterin resulted in clinically significant and sustained reductions in blood Phe concentrations and increased dietary Phe tolerance in well-designed clinical studies in PKU patients who responded to BH4. Successful treatment with sapropterin may lead to a relaxation of the Phe-restricted diet, although continued monitoring of blood Phe is required. Sapropterin was well tolerated.
Diagnosis, classification, and genetics of phenylketonuria and tetrahydrobiopterin (BH4) deficiencies
Mol Genet Metab 2011;104 Suppl:S2-9.PMID:21937252DOI:10.1016/j.ymgme.2011.08.017.
This article summarizes the present knowledge, recent developments, and common pitfalls in the diagnosis, classification, and genetics of hyperphenylalaninemia, including tetrahydrobiopterin (BH4) deficiency. It is a product of the recent workshop organized by the European Phenylketonuria Group in March 2011 in Lisbon, Portugal. Results of the workshop demonstrate that following newborn screening for phenylketonuria (PKU), using tandem mass-spectrometry, every newborn with even slightly elevated blood phenylalanine (Phe) levels needs to be screened for BH4 deficiency. Dried blood spots are the best sample for the simultaneous measurement of amino acids (phenylalanine and tyrosine), pterins (neopterin and biopterin), and dihydropteridine reductase activity from a single specimen. Following diagnosis, the patient's phenotype and individually tailored treatment should be established as soon as possible. Not only blood Phe levels, but also daily tolerance for dietary Phe and potential responsiveness to BH4 are part of the investigations. Efficiency testing with synthetic BH4 (Sapropterin dihydrochloride) over several weeks should follow the initial 24-48-hour screening test with 20mg/kg/day BH4. The specific genotype, i.e. the combination of both PAH alleles of the patient, helps or facilitates to determine both the biochemical phenotype (severity of PKU) and the responsiveness to BH4. The rate of Phe metabolic disposal after Phe challenge may be an additional useful tool in the interpretation of phenotype-genotype correlation.