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Sapropterin dihydrochloride (6R-BH4 dihydrochloride) Sale

(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

Sapropterin dihydrochloride (6R-BH4 dihydrochloride) Chemical Structure

Cas No.:69056-38-8

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10mM (in 1mL Water)
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50mg
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产品描述

(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)

Chemical Properties

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
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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
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Research Update

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.