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Details

Stereochemistry ABSOLUTE
Molecular Formula C9H15N5O3
Molecular Weight 241.2475
Optical Activity UNSPECIFIED
Defined Stereocenters 3 / 3
E/Z Centers 0
Charge 0

SHOW SMILES / InChI
Structure of SAPROPTERIN

SMILES

C[C@@]([H])([C@@]([H])([C@@]1([H])CNc2c(c(nc(=N)[nH]2)O)N1)O)O

InChI

InChIKey=FNKQXYHWGSIFBK-RPDRRWSUSA-N
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

HIDE SMILES / InChI

Description
Curator's Comment:: http://www.biomarin.com/products/kuvan

Sapropterin dihydrochloride, the active pharmaceutical ingredient in Kuvan Tablets, is a synthetic preparation of the dihydrochloride salt of naturally occurring tetrahydrobiopterin (BH4). Kuvan is indicated to reduce blood phenylalanine (Phe) levels in patients with hyperphenylalaninemia (HPA) due to tetrahydrobiopterin- (BH4-) responsive Phenylketonuria (PKU). Kuvan is to be used in conjunction with a Phe-restricted diet. Kuvan has received orphan drug designation from both the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMEA). Kuvan is a synthetic form of BH4, the cofactor for the enzyme phenylalanine hydroxylase (PAH). PAH hydroxylates Phe through an oxidative reaction to form tyrosine. In patients with PKU, PAH activity is absent or deficient. Treatment with BH4 can activate residual PAH enzyme, improve the normal oxidative metabolism of Phe, and decrease Phe levels in some patients.

Originator

Curator's Comment:: Asubio Pharma (a US-based independent subsidiary of Daiichi Sankyo)

Approval Year

Targets

Targets

Conditions

Conditions

ConditionModalityTargetsHighest PhaseProduct
Primary
KUVAN

Approved Use

Kuvan® (sapropterin dihydrochloride) is indicated to reduce blood phenylalanine (Phe) levels in patients with hyperphenylalaninemia (HPA) due to tetrahydrobiopterin- (BH4-) responsive Phenylketonuria (PKU). Kuvan is to be used in conjunction with a Phe-restricted diet. Kuvan is a phenylalanine hydroxylase activator indicated to reduce blood phenylalanine (Phe) levels in patients with hyperphenylalaninemia (HPA) due to tetrahydrobiopterin‑ (BH4‑) responsive Phenylketonuria (PKU). Kuvan is to be used in conjunction with a Phe‑restricted diet (1).

Launch Date

1197504000000
Cmax

Cmax

ValueDoseCo-administeredAnalytePopulation
84.1 ng/mL
10 mg/kg single, oral
dose: 10 mg/kg
route of administration: Oral
experiment type: SINGLE
co-administered:
SAPROPTERIN plasma
Homo sapiens
population: HEALTHY
age: ADULT
sex: FEMALE / MALE
food status: FASTED
AUC

AUC

ValueDoseCo-administeredAnalytePopulation
559 ng × h/mL
10 mg/kg single, oral
dose: 10 mg/kg
route of administration: Oral
experiment type: SINGLE
co-administered:
SAPROPTERIN plasma
Homo sapiens
population: HEALTHY
age: ADULT
sex: FEMALE / MALE
food status: FASTED
T1/2

T1/2

ValueDoseCo-administeredAnalytePopulation
3.67 h
10 mg/kg single, oral
dose: 10 mg/kg
route of administration: Oral
experiment type: SINGLE
co-administered:
SAPROPTERIN plasma
Homo sapiens
population: HEALTHY
age: ADULT
sex: FEMALE / MALE
food status: FASTED
Doses

Doses

DosePopulationAdverse events​
20 mg/kg 1 times / day multiple, oral
Recommended
Dose: 20 mg/kg, 1 times / day
Route: oral
Route: multiple
Dose: 20 mg/kg, 1 times / day
Sources:
unhealthy, 7.7
Health Status: unhealthy
Age Group: 7.7
Sex: M+F
Sources:
45 mg/kg single, oral
Overdose
Dose: 45 mg/kg
Route: oral
Route: single
Dose: 45 mg/kg
Sources:
unhealthy, child
Disc. AE: Hyperactivity...
AEs leading to
discontinuation/dose reduction:
Hyperactivity
Sources:
20 mg/kg 1 times / day multiple, oral
Recommended
Dose: 20 mg/kg, 1 times / day
Route: oral
Route: multiple
Dose: 20 mg/kg, 1 times / day
Sources:
unhealthy
Disc. AE: Hypersensitivity reaction, Anaphylaxis...
AEs leading to
discontinuation/dose reduction:
Hypersensitivity reaction
Anaphylaxis
Gastritis
Hyperactivity
Sources:
AEs

AEs

AESignificanceDosePopulation
Hyperactivity Disc. AE
45 mg/kg single, oral
Overdose
Dose: 45 mg/kg
Route: oral
Route: single
Dose: 45 mg/kg
Sources:
unhealthy, child
Anaphylaxis Disc. AE
20 mg/kg 1 times / day multiple, oral
Recommended
Dose: 20 mg/kg, 1 times / day
Route: oral
Route: multiple
Dose: 20 mg/kg, 1 times / day
Sources:
unhealthy
Gastritis Disc. AE
20 mg/kg 1 times / day multiple, oral
Recommended
Dose: 20 mg/kg, 1 times / day
Route: oral
Route: multiple
Dose: 20 mg/kg, 1 times / day
Sources:
unhealthy
Hyperactivity Disc. AE
20 mg/kg 1 times / day multiple, oral
Recommended
Dose: 20 mg/kg, 1 times / day
Route: oral
Route: multiple
Dose: 20 mg/kg, 1 times / day
Sources:
unhealthy
Hypersensitivity reaction Disc. AE
20 mg/kg 1 times / day multiple, oral
Recommended
Dose: 20 mg/kg, 1 times / day
Route: oral
Route: multiple
Dose: 20 mg/kg, 1 times / day
Sources:
unhealthy
Overview

Overview

CYP3A4CYP2C9CYP2D6hERG

OverviewOther

Drug as perpetrator​Drug as victim

Drug as victim

TargetModalityActivityMetaboliteClinical evidence
no
Tox targets

Tox targets

TargetModalityActivityMetaboliteClinical evidence
PubMed

PubMed

TitleDatePubMed
Tetrahydrobiopterin binding to aromatic amino acid hydroxylases. Ligand recognition and specificity.
2004 Nov 18
Patents

Sample Use Guides

The recommended starting dose is 10 mg/kg/day taken once daily. Response to therapy is determined by change in blood Phe following treatment with drug at 10 mg/kg/day for a period of up to 1 month. Blood Phe levels should be checked after 1 week of treatment and periodically for up to a month. If blood Phe does not decrease from baseline at 10 mg/kg/day, the dose may be increased to 20 mg/kg/day. Patients whose blood Phe does not decrease after 1 month of treatment at 20 mg/kg/day are non-responders, and treatment should be discontinued in these patients. Once responsiveness to drug has been established, the dosage may be adjusted within the range of 5 to 20 mg/kg/day according to response to therapy. Doses above 20 mg/kg/day have not been evaluated in clinical trials.
Route of Administration: Oral
In Vitro Use Guide
The effect of tetrahydrobiopterin (BH4, SAPROPTERIN) on subunit structure and activity of microsomal and cytosolic Type III nitric oxide synthase (NOS III) was compared. BH4 activates NOS III in the primordial human placenta by promoting its subunit assembly in the membrane, while cytosolic NOS III is relatively insensitive to BH4. Incubation of microsomal membranes with 50 microM final concentration BH4 for 10 min at 37 degrees C resulted in a striking conversion of monomeric NOS III into a protein having the characteristics (electrophoretic mobility, resistance to sodium dodecyl sulphate) of the homodimeric form. In contrast, BH4 induced significantly less marked changes in the NOS III dimer content of cytosolic fractions. Enzyme activity in microsomes is stimulated approximately 6-fold upon addition of 50 microM BH4, while only a 2-fold activation is detectable in cytosolic fractions.
Name Type Language
SAPROPTERIN
INN   MI   VANDF   WHO-DD  
INN  
Official Name English
R-THBP
Common Name English
SAPROPTERIN [MI]
Common Name English
(6R)-2-AMINO-6-((1R,2S)-1,2-DIHYDROXYPROPYL)-5,6,7,8-TETRAHYDROPTERIDIN-4(1H)-ONE
Systematic Name English
BH4
Common Name English
SAPROPTERIN [VANDF]
Common Name English
6R-BH4
Common Name English
DAPROPTERIN
Common Name English
TETRAHYDROBIOPTERIN
Common Name English
4(1H)-PTERIDINONE, (6R)-2-AMINO-6-((1R,2S)-1,2-DIHYDROXYPROPYL)-5,6,7,8-TETRAHYDRO-
Systematic Name English
(6R)-L-ERYTHRO-TETRAHYDROBIOPTERIN
Common Name English
SAPROPTERIN [WHO-DD]
Common Name English
SAPROPTERIN [INN]
Common Name English
(6R)-2-AMINO-6-((1R,2S)-1,2-DIHYDROXYPROPYL)-5,6,7,8-TETRAHYDRO-4(1H)-PTERIDINONE
Systematic Name English
Classification Tree Code System Code
LOINC 59247-7
Created by admin on Sat Jun 26 13:23:13 UTC 2021 , Edited by admin on Sat Jun 26 13:23:13 UTC 2021
LOINC 33877-2
Created by admin on Sat Jun 26 13:23:13 UTC 2021 , Edited by admin on Sat Jun 26 13:23:13 UTC 2021
WHO-ATC A16AX07
Created by admin on Sat Jun 26 13:23:13 UTC 2021 , Edited by admin on Sat Jun 26 13:23:13 UTC 2021
NCI_THESAURUS C275
Created by admin on Sat Jun 26 13:23:13 UTC 2021 , Edited by admin on Sat Jun 26 13:23:13 UTC 2021
WHO-VATC QA16AX07
Created by admin on Sat Jun 26 13:23:13 UTC 2021 , Edited by admin on Sat Jun 26 13:23:13 UTC 2021
NDF-RT N0000190483
Created by admin on Sat Jun 26 13:23:13 UTC 2021 , Edited by admin on Sat Jun 26 13:23:13 UTC 2021
FDA ORPHAN DRUG 181503
Created by admin on Sat Jun 26 13:23:13 UTC 2021 , Edited by admin on Sat Jun 26 13:23:13 UTC 2021
EU-Orphan Drug EU/3/05/308
Created by admin on Sat Jun 26 13:23:13 UTC 2021 , Edited by admin on Sat Jun 26 13:23:13 UTC 2021
NCI_THESAURUS C1916
Created by admin on Sat Jun 26 13:23:13 UTC 2021 , Edited by admin on Sat Jun 26 13:23:13 UTC 2021
Code System Code Type Description
CAS
62989-33-7
Created by admin on Sat Jun 26 13:23:13 UTC 2021 , Edited by admin on Sat Jun 26 13:23:13 UTC 2021
PRIMARY
LACTMED
Sapropterin
Created by admin on Sat Jun 26 13:23:13 UTC 2021 , Edited by admin on Sat Jun 26 13:23:13 UTC 2021
PRIMARY
ChEMBL
CHEMBL1201774
Created by admin on Sat Jun 26 13:23:13 UTC 2021 , Edited by admin on Sat Jun 26 13:23:13 UTC 2021
PRIMARY
NDF-RT
N0000190482
Created by admin on Sat Jun 26 13:23:13 UTC 2021 , Edited by admin on Sat Jun 26 13:23:13 UTC 2021
PRIMARY Phenylalanine Hydroxylase Activators [MoA]
DRUG BANK
DB00360
Created by admin on Sat Jun 26 13:23:13 UTC 2021 , Edited by admin on Sat Jun 26 13:23:13 UTC 2021
PRIMARY
CAS
17528-72-2
Created by admin on Sat Jun 26 13:23:13 UTC 2021 , Edited by admin on Sat Jun 26 13:23:13 UTC 2021
NON-SPECIFIC STEREOCHEMISTRY
IUPHAR
5276
Created by admin on Sat Jun 26 13:23:13 UTC 2021 , Edited by admin on Sat Jun 26 13:23:13 UTC 2021
PRIMARY
INN
6553
Created by admin on Sat Jun 26 13:23:13 UTC 2021 , Edited by admin on Sat Jun 26 13:23:13 UTC 2021
PRIMARY
WIKIPEDIA
TETRAHYDROBIOPTERIN
Created by admin on Sat Jun 26 13:23:13 UTC 2021 , Edited by admin on Sat Jun 26 13:23:13 UTC 2021
PRIMARY
NCI_THESAURUS
C78087
Created by admin on Sat Jun 26 13:23:13 UTC 2021 , Edited by admin on Sat Jun 26 13:23:13 UTC 2021
PRIMARY
RXCUI
753340
Created by admin on Sat Jun 26 13:23:13 UTC 2021 , Edited by admin on Sat Jun 26 13:23:13 UTC 2021
PRIMARY RxNorm
NDF-RT
N0000190113
Created by admin on Sat Jun 26 13:23:13 UTC 2021 , Edited by admin on Sat Jun 26 13:23:13 UTC 2021
PRIMARY Breast Cancer Resistance Protein Inhibitors [MoA]
EPA CompTox
17528-72-2
Created by admin on Sat Jun 26 13:23:13 UTC 2021 , Edited by admin on Sat Jun 26 13:23:13 UTC 2021
PRIMARY
PUBCHEM
135398654
Created by admin on Sat Jun 26 13:23:13 UTC 2021 , Edited by admin on Sat Jun 26 13:23:13 UTC 2021
PRIMARY
EVMPD
SUB10445MIG
Created by admin on Sat Jun 26 13:23:13 UTC 2021 , Edited by admin on Sat Jun 26 13:23:13 UTC 2021
PRIMARY
CAS
27070-47-9
Created by admin on Sat Jun 26 13:23:13 UTC 2021 , Edited by admin on Sat Jun 26 13:23:13 UTC 2021
ALTERNATIVE
MERCK INDEX
M9775
Created by admin on Sat Jun 26 13:23:13 UTC 2021 , Edited by admin on Sat Jun 26 13:23:13 UTC 2021
PRIMARY Merck Index
NDF-RT
N0000185503
Created by admin on Sat Jun 26 13:23:13 UTC 2021 , Edited by admin on Sat Jun 26 13:23:13 UTC 2021
PRIMARY P-Glycoprotein Inhibitors [MoA]
DRUG CENTRAL
2612
Created by admin on Sat Jun 26 13:23:13 UTC 2021 , Edited by admin on Sat Jun 26 13:23:13 UTC 2021
PRIMARY
FDA UNII
EGX657432I
Created by admin on Sat Jun 26 13:23:13 UTC 2021 , Edited by admin on Sat Jun 26 13:23:13 UTC 2021
PRIMARY