SAPROPTERIN SESQUIHYDROCHLORIDE

Details

Stereochemistry	ABSOLUTE
Molecular Formula	2C9H15N5O3.3ClH
Molecular Weight	591.877
Optical Activity	UNSPECIFIED
Defined Stereocenters	6 / 6
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure of SAPROPTERIN SESQUIHYDROCHLORIDE

Structure Search

SMILES

Cl.Cl.Cl.[H][C@@]1(CNC2=C(N1)C(=O)NC(N)=N2)[C@@H](O)[C@H](C)O.[H][C@@]3(CNC4=C(N3)C(=O)NC(N)=N4)[C@@H](O)[C@H](C)O

InChI

InChIKey=IQNRAURJGSOFCP-KHAAUVMPSA-N

InChI=1S/2C9H15N5O3.3ClH/c2*1-3(15)6(16)4-2-11-7-5(12-4)8(17)14-9(10)13-7;;;/h2*3-4,6,12,15-16H,2H2,1H3,(H4,10,11,13,14,17);3*1H/t2*3-,4+,6-;;;/m00.../s1

HIDE SMILES / InChI

Description
Sources: http://www.accessdata.fda.gov/drugsatfda_docs/label/2007/022181lbl.pdf
Curator's Comment: description was created based on several sources, including 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.

CNS Activity

Originator

Approval Year

Targets

Primary Target	Pharmacology	Condition	Potency
Phenylalanine-4-hydroxylase 9 Target ID: CHEMBL3076 Sources: https://www.ncbi.nlm.nih.gov/pubmed/10872454	Substrate 661
Nitric-oxide synthase, endothelial 19 Target ID: CHEMBL4803 Sources: https://www.ncbi.nlm.nih.gov/pubmed/12003347	Substrate 661

Conditions

Condition	Modality	Targets	Highest Phase	Product
Phenylketonuria 5 Sources: http://www.accessdata.fda.gov/drugsatfda_docs/label/2007/022181lbl.pdf	Primary		Approved 8429	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 2007

C_max

Value	Dose	Co-administered	Analyte	Population
84.1 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/20206791/	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

Value	Dose	Co-administered	Analyte	Population
559 ng × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/20206791/	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

T_1/2

Value	Dose	Co-administered	Analyte	Population
3.67 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/20206791/	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

Dose	Population	Adverse 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: https://pubmed.ncbi.nlm.nih.gov/19261295 Page: p.705	unhealthy, 7.7 n = 33 Health Status: unhealthy Condition: Phenylketonuria Age Group: 7.7 Sex: M+F Population Size: 33 Sources: https://pubmed.ncbi.nlm.nih.gov/19261295 Page: p.705	Sources: https://pubmed.ncbi.nlm.nih.gov/19261295 Page: p.705
45 mg/kg single, oral Overdose Dose: 45 mg/kg Route: oral Route: single Dose: 45 mg/kg Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/022181s013lbl.pdf Page: p.10	unhealthy, child n = 1 Health Status: unhealthy Condition: Hyperphenylalaninemia (HPA) due to tetrahydrobiopterin- (BH4 -) responsive Phenylketonuria Age Group: child Population Size: 1 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/022181s013lbl.pdf Page: p.10	Disc. AE: Hyperactivity... AEs leading to discontinuation/dose reduction: Hyperactivity Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/022181s013lbl.pdf Page: p.10
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: https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/022181s013lbl.pdf Page: p.1	unhealthy Health Status: unhealthy Condition: Hyperphenylalaninemia (HPA) due to tetrahydrobiopterin- (BH4 -) responsive Phenylketonuria Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/022181s013lbl.pdf Page: p.1	Disc. AE: Hypersensitivity reaction, Anaphylaxis... AEs leading to discontinuation/dose reduction: Hypersensitivity reaction Anaphylaxis Gastritis Hyperactivity Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/022181s013lbl.pdf Page: p.1

AEs

AE	Significance	Dose	Population
Hyperactivity	Disc. AE	45 mg/kg single, oral Overdose Dose: 45 mg/kg Route: oral Route: single Dose: 45 mg/kg Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/022181s013lbl.pdf Page: p.10	unhealthy, child n = 1 Health Status: unhealthy Condition: Hyperphenylalaninemia (HPA) due to tetrahydrobiopterin- (BH4 -) responsive Phenylketonuria Age Group: child Population Size: 1 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/022181s013lbl.pdf Page: p.10
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: https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/022181s013lbl.pdf Page: p.1	unhealthy Health Status: unhealthy Condition: Hyperphenylalaninemia (HPA) due to tetrahydrobiopterin- (BH4 -) responsive Phenylketonuria Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/022181s013lbl.pdf Page: p.1
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: https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/022181s013lbl.pdf Page: p.1	unhealthy Health Status: unhealthy Condition: Hyperphenylalaninemia (HPA) due to tetrahydrobiopterin- (BH4 -) responsive Phenylketonuria Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/022181s013lbl.pdf Page: p.1
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: https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/022181s013lbl.pdf Page: p.1	unhealthy Health Status: unhealthy Condition: Hyperphenylalaninemia (HPA) due to tetrahydrobiopterin- (BH4 -) responsive Phenylketonuria Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/022181s013lbl.pdf Page: p.1
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: https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/022181s013lbl.pdf Page: p.1	unhealthy Health Status: unhealthy Condition: Hyperphenylalaninemia (HPA) due to tetrahydrobiopterin- (BH4 -) responsive Phenylketonuria Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/022181s013lbl.pdf Page: p.1

Overview

CYP3A4	CYP2C9	CYP2D6	hERG
			inhibitor 1612

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
OAT1 599 CYP 111 OAT3 642 OCT2 647 MATE1 306 MATE2 263 OATP1B1 788 OATP1B3 706 BCRP 699	CYP 270

Drug as perpetrator

Target	Modality	Activity
OATP1B1 803	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/022181s020,205065s006lbl.pdf Page: 15.0	inconclusive
OATP1B3 715	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/022181s020,205065s006lbl.pdf Page: 15.0	inconclusive
CYP 147	activator 214 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2007/022181s000_PharmR_P1.pdf Page: 13.0	no
CYP 147	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2007/022181s000_PharmR_P1.pdf Page: 13.0	no
MATE1 308	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/022181s020,205065s006lbl.pdf Page: 15.0	no
MATE2 263	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/022181s020,205065s006lbl.pdf Page: 15.0	no
OAT1 603	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/022181s020,205065s006lbl.pdf Page: 15.0	no
OAT3 644	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/022181s020,205065s006lbl.pdf Page: 15.0	no
OCT2 648	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/022181s020,205065s006lbl.pdf Page: 15.0	no
BCRP 773	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/022181s020,205065s006lbl.pdf Page: 15.0	yes

Drug as victim

Target	Modality	Activity	Metabolite	Clinical evidence
CYP 270	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2007/022181s000_PharmR_P2.pdf Page: 4.0	no

Tox targets

Target	Modality	Activity	Metabolite	Clinical evidence
hERG 1647	inhibitor 1626 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2007/022181s000_PharmR_P1.pdf Page: 39, 40

Sourcing

Vendor/Aggregator	ID	URL
ChEBI	CHEBI:59560	https://www.ebi.ac.uk/chebi/searchId.do?chebiId=CHEBI:59560
ChemicalBook	CB5479898	https://www.chemicalbook.com/ChemicalProductProperty_EN_CB5479898
ZINC	ZINC000013585233	http://zinc15.docking.org/substances/ZINC000013585233
eMolecules	31240471	https://www.emolecules.com/cgi-bin/more?vid=31240471

PubMed

Title	Date	PubMed
Tetrahydrobiopterin binding to aromatic amino acid hydroxylases. Ligand recognition and specificity.	2004 Nov 18	15537351
New era in treatment for phenylketonuria: Pharmacologic therapy with sapropterin dihydrochloride.	2010 Aug 9	20714359

Patents

Sample Use Guides

In Vivo Use Guide

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 SESQUIHYDROCHLORIDE

Common Name

English

4(1H)-PTERIDINONE, 2-AMINO-6-(1,2-DIHYDROXYPROPYL)-5,6,7,8-TETRAHYDRO-, HYDROCHLORIDE (2:3), (6R-(6R*(1R*,2S*)))-

Common Name

English

Code System Code Type Description

FDA UNII

F774380N1W