sapropterin   Click here for help

GtoPdb Ligand ID: 5276

Synonyms: Kuvan® | sapropterin dihydrochloride | SUN-0588 | T-1401 | tetrahydrobiopterin (THB)
Approved drug PDB Ligand Immunopharmacology Ligand
sapropterin is an approved drug (FDA (2007), EMA (2008))
Compound class: Metabolite
Comment: Sapropterin (also known as tetrahydrobiopterin or BH4) is an essential enzymatic cofactor for aromatic amino acid hydroxylase enzymes; phenylalanine hydroxylase (PAH), tryptophan hydroxylase, tyrosine hydroxylase and for nitric oxide synthase. It is used by PAH to degrade phenylalanine, and is required for the biosynthesis of the neurotransmitters serotonin, melatonin, dopamine, norepinephrine (noradrenaline) and epinephrine (adrenaline).
Sapropterin is produced via a pathway of reactions catalysed by the enzymes GTP cyclohydrolase I (GCH1; the primary and rate-limiting reaction), 6-pyruvoyltetrahydropterin synthase (PTPS) and sepiapterin reductase (SR; the terminal reaction).
Click here for help

Ligand Activity Visualisation Charts

These are box plot that provide a unique visualisation, summarising all the activity data for a ligand taken from ChEMBL and GtoPdb across multiple targets and species. Click on a plot to see the median, interquartile range, low and high data points. A value of zero indicates that no data are available. A separate chart is created for each target, and where possible the algorithm tries to merge ChEMBL and GtoPdb targets by matching them on name and UniProt accession, for each available species. However, please note that inconsistency in naming of targets may lead to data for the same target being reported across multiple charts.

✖

View interactive charts of activity data across species
2D Structure
Click here for help

2D Structure

An image of the ligand's 2D structure. For small molecules with SMILES these are drawn using the NCI/CADD Chemical Identifier Resolver. Click on the image to access the chemical structure search tool with the ligand pre-loaded in the structure editor. For other types of ligands, e.g. longer nucleotides and peptides, a manually drawn representation of the molecule may be provided.

✖
Click here for structure editor
Physico-chemical Properties
Click here for help

Physico-chemical Properties

Calculated molecular properties are available for small molecules and natural products (not peptides). Properties were generated using the Chemistry Development Kit (CDK) (Willighagen EL et al. Journal of Cheminformatics vol. 9:33. 2017, doi:10.1186/s13321-017-0220-4; https://cdk.github.io/). All properties were selected to enable the prediction of the Lipinski Rule-of-Five profile or ‘druglikeness’ for each ligand. For more info on each category see the help pages.

✖
Hydrogen bond acceptors 7
Hydrogen bond donors 6
Rotatable bonds 2
Topological polar surface area 136.29
Molecular weight 241.12
XLogP -0.1
No. Lipinski's rules broken 1

Generated using the Chemistry Development Kit (CDK) (Willighagen EL et al. Journal of Cheminformatics vol. 9:33. 2017, doi:10.1186/s13321-017-0220-4; https://cdk.github.io/)
SMILES / InChI / InChIKey
Click here for help

SMILES / InChI / InChIKey

SMILES (Simplified Molecular Input Line Entry Specification) A specification for unambiguously describing the structure of chemical molecules using short ASCII strings. Canonical SMILES specify a unique representation of the 2D structure without chiral or isotopic specifications. Isomeric SMILES include chiral specification and isotopes.

Standard InChI (IUPAC International Chemical Identifier) and InChIKey InChI is a non-proprietary, standard, textual identifier for chemical substances designed to facilitate linking of information and database searching. An InChIKey is a simplified version of a full InChI, designed for easier web searching.

Generated using the Chemistry Development Kit (CDK) (Willighagen EL et al. Journal of Cheminformatics vol. 9:33. 2017, doi:10.1186/s13321-017-0220-4; https://cdk.github.io/)

✖
Canonical SMILES CC(C(C1CNc2c(N1)c(=O)[nH]c(n2)N)O)O
Isomeric SMILES C[C@@H]([C@@H]([C@H]1CNc2c(N1)c(=O)[nH]c(n2)N)O)O
InChI InChI=1S/C9H15N5O3/c1-3(15)6(16)4-2-11-7-5(12-4)8(17)14-9(10)13-7/h3-4,6,12,15-16H,2H2,1H3,(H4,10,11,13,14,17)/t3-,4+,6-/m0/s1
InChI Key FNKQXYHWGSIFBK-RPDRRWSUSA-N

Generated using the Chemistry Development Kit (CDK) (Willighagen EL et al. Journal of Cheminformatics vol. 9:33. 2017, doi:10.1186/s13321-017-0220-4; https://cdk.github.io/)
No information available.
Summary of Clinical Use Click here for help
This drug is used alongside a low-phenylalanine diet to treat patients with phenylketonuria [1], as it acts to control blood levels of phenylalanine in some patients. It can also be used to treat dopamine-responsive dystonia which can result from BH4 deficiency (due to defects in the BH4 biosynthetic pathway) and subsequent lack of dopamine biosynthesis.
Mechanism Of Action and Pharmacodynamic Effects Click here for help
Phenylalanine hydroxylase (PAH) deficiency causes phenylketonuria (characterised by elevated blood phenylalanine). Supplying additional BH4 (a PAH co-factor) is predicted to optimise residual PAH activity, to bring about a reduction in circulating phenylalanine. Elevated phenylalanine levels are associated with the intellectual and developmental disabilities observed in phenylketonuria patients.

PAH-catalysed conversion of phenylalanine to tyrosine is required for the production of epinephrine (adrenaline) and the synthesis of the neuro-transmitters, serotonin, dopamine, and norepinephrine (noradrenaline). It is also involved in apoptosis and other cellular events mediated by nitric oxide production.
External links Click here for help
For extended ADME data see the following:

Electronic Medicines Compendium (eMC)
Drugs.com
European Medicines Agency (EMA)