FOSDENOPTERIN

Details

Stereochemistry	ABSOLUTE
Molecular Formula	C10H14N5O8P
Molecular Weight	363.221
Optical Activity	UNSPECIFIED
Defined Stereocenters	4 / 4
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

SMILES

[H][C@@]12COP(O)(=O)O[C@]1([H])C(O)(O)[C@]3([H])NC4=C(NC(N)=NC4=O)N[C@]3([H])O2

InChI

InChIKey=CZAKJJUNKNPTTO-AJFJRRQVSA-N

InChI=1S/C10H14N5O8P/c11-9-14-6-3(7(16)15-9)12-4-8(13-6)22-2-1-21-24(19,20)23-5(2)10(4,17)18/h2,4-5,8,12,17-18H,1H2,(H,19,20)(H4,11,13,14,15,16)/t2-,4-,5+,8-/m1/s1

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Description

Fosdenopterin (NulibryTM) is a synthetic cyclic pyranopterin monophosphate that is being developed by Origin Biosciences (a subsidiary of BridgeBio Pharma) for the treatment of molybdenum cofactor deficiency (MoCD) type A. Patients with MoCD Type A have mutations in the MOCS1 gene leading to deficient MOCS1A/B dependent synthesis of the intermediate substrate, cPMP. Substrate replacement therapy with NULIBRY provides an exogenous source of cPMP, which is converted to molybdopterin. Molybdopterin is then converted to molybdenum cofactor, which is needed for the activation of molybdenum-dependent enzymes, including sulfite oxidase (SOX), an enzyme that reduces levels of neurotoxic sulfites. Fosdenopterin was approved by the US FDA in February 2021 for use in reducing the risk of mortality in paediatric and adult patients with MoCD type A.

CNS Activity

Approval Year

Targets

Primary Target	Pharmacology	Condition	Potency
Molybdopterin synthase catalytic subunit 3	Substrate 661

Conditions

Condition	Modality	Targets	Highest Phase	Product
molybdenum cofactor deficiency Type A 3	Primary		Approved 8,583	NULIBRY

C_max

Value	Dose	Analyte	Population
285 ng/mL	0.075 mg/kg single, intravenous	CYCLIC PYRANOPTERIN MONOPHOSPHATE plasma	Homo sapiens
873 ng/mL	0.25 mg/kg single, intravenous	CYCLIC PYRANOPTERIN MONOPHOSPHATE plasma	Homo sapiens
2800 ng/mL	0.68 mg/kg single, intravenous	CYCLIC PYRANOPTERIN MONOPHOSPHATE plasma	Homo sapiens

AUC

Value	Dose	Analyte	Population
523 ng × h/mL	0.075 mg/kg single, intravenous	CYCLIC PYRANOPTERIN MONOPHOSPHATE plasma	Homo sapiens
1790 ng × h/mL	0.25 mg/kg single, intravenous	CYCLIC PYRANOPTERIN MONOPHOSPHATE plasma	Homo sapiens
5960 ng × h/mL	0.68 mg/kg single, intravenous	CYCLIC PYRANOPTERIN MONOPHOSPHATE plasma	Homo sapiens

T_1/2

Value	Dose	Analyte	Population
1.22 h	0.075 mg/kg single, intravenous	CYCLIC PYRANOPTERIN MONOPHOSPHATE plasma	Homo sapiens
1.67 h	0.25 mg/kg single, intravenous	CYCLIC PYRANOPTERIN MONOPHOSPHATE plasma	Homo sapiens
1.64 h	0.68 mg/kg single, intravenous	CYCLIC PYRANOPTERIN MONOPHOSPHATE plasma	Homo sapiens

F_unbound

Value	Dose	Co-administered	Analyte	Population
87.6%			CYCLIC PYRANOPTERIN MONOPHOSPHATE plasma	Homo sapiens

Doses

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Dose	Population	Adverse events
1300 ug/kg/day 1 times / day multiple, intravenous Studied dose	unhealthy, NEWBORN\|CHILD	Disc. AE: Adverse event, Adverse event... Other AEs: Respiratory tract infection, Pyrexia...

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AEs

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AE	Significance	Dose	Population
Adverse event	0% Disc. AE	1300 ug/kg/day 1 times / day multiple, intravenous Studied dose	unhealthy, NEWBORN\|CHILD
Adverse event	0% Disc. AE	1300 ug/kg/day 1 times / day multiple, intravenous Studied dose	unhealthy, NEWBORN\|CHILD
Respiratory tract infection	Serious, 1 patient	1300 ug/kg/day 1 times / day multiple, intravenous Studied dose	unhealthy, NEWBORN\|CHILD
Device leakage	Serious, 1 pt	1300 ug/kg/day 1 times / day multiple, intravenous Studied dose	unhealthy, NEWBORN\|CHILD
Infection	Serious, 1 pt	1300 ug/kg/day 1 times / day multiple, intravenous Studied dose	unhealthy, NEWBORN\|CHILD

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Overview

CYP3A4	CYP2C9	CYP2D6	hERG
	substrate 1,193 inducer 440 inhibitor 2,438	inhibitor 2,507 substrate 1,388	inhibitor 2,217

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
BCRP 910 CYP2B6 926 OATP1B3 961 CYP2C19 2,057 OCT2 779 OATP1B1 1,079 CYP3A4/5 296 OAT1 725 CYP1A2 2,153 P-gp 1,741 CYP2C8 1,057 MATE2-K 77 MATE1 415 OAT3 747 Cav1.2 58 Nav1.5 116	CYP1A2 1,197 CYP2B6 776 CYP2C8 810 BCRP 697 OAT3 391 OCT2 434 OATP1B1 503 CYP2C19 1,119 MATE2-K 33 CYP3A4/5 91 OAT1 395 P-gp 2,052 OATP1B3 435 MATE1 182	CYP1A2 832 CYP3A4/5 133 CYP2C19 329 CYP2C8 198 CYP2B6 669

Drug as perpetrator

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Target	Modality	Activity
BCRP 985	inhibitor 4,027	no [IC50 >200 uM]
MATE1 416	inhibitor 4,027	no [IC50 >200 uM]
OAT3 749	inhibitor 4,027	no [IC50 >200 uM]
OATP1B1 1,095	inhibitor 4,027	no [IC50 >200 uM]
OATP1B3 970	inhibitor 4,027	no [IC50 >200 uM]

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Drug as victim

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Target	Modality	Activity
BCRP 697	substrate 4,014	no
CYP1A2 1,197	substrate 4,014	no
CYP2B6 776	substrate 4,014	no
CYP2C19 1,119	substrate 4,014	no
CYP2C8 810	substrate 4,014	no

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Tox targets

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Target	Modality	Activity	Metabolite	Clinical evidence
Cav1.2 63	inhibitor 2,237
Nav1.5 119	inhibitor 2,237
hERG 2,263	inhibitor 2,237

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PubMed

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Title	Date	PubMed
Molybdenum Cofactor Deficiency.	1993	34870926
Fosdenopterin: First Approval.	2021 Jun	33909276
Regulatory news: Nulibry (fosdenopterin) approved to reduce the risk of mortality in patients with molybdenum cofactor deficiency type A: FDA approval summary.	2021 Sep	34337775

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Patents

Sample Use Guides

In Vivo Use Guide

Administer as an intravenous infusion once daily at a rate of 1.5 mL/minute with non-DEHP tubing with a 0.2 micron filter. Volumes below 2 mL may require syringe administration through slow intravenous push. Initial dosage (preterm neonates): 0.4 mg/kg once daily; Initial dosage (term neonates): 0.55 mg/kg once daily; Month 1 (preterm neonates): 0.7 mg/kg once daily; Month 1 (term neonates): 0.75 mg/kg once daily; Month 3 (preterm neonates): 0.9 mg/kg once daily; Month 3 (term neonates): 0.9 mg/kg once daily.

Route of Administration: Intravenous

In Vitro Use Guide

Fosdenopterin had no inhibitory effect on a variety of ion channels tested in an in vitro panel, with IC50 values >300uM.

Show entries

Name

Type

Language

CYCLIC PYRANOPTERIN MONOPHOSPHATE

Preferred Name

English

FOSDENOPTERIN

Official Name

English

ALXN-1101 ANHYDROUS FREE BASE

Code

English

PRECURSOR Z

Common Name

English

C(PMP)

Common Name

English

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Classification Tree

Code System

Code

Designated/Approved

FDA ORPHAN DRUG

291209

Positive

EU-Orphan Drug

EU/3/10/777

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Code System

Code

Type

Description

RXCUI

2531288

PRIMARY

CAS

150829-29-1

PRIMARY

EVMPD

SUB197148

PRIMARY

NCI_THESAURUS

C175065

PRIMARY

SMS_ID

100000182803

PRIMARY

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ACTIVE MOIETY


					4X7K2681Y7

FOSDENOPTERIN

METABOLITE ACTIVE (PARENT)


					EPP8L4V5E3

MOLYBDOPTERIN

SALT/SOLVATE (PARENT)


					8Y2YH219A9

FOSDENOPTERIN HYDROBROMIDE ANHYDROUS

SALT/SOLVATE (PARENT)


					X41B5W735T

FOSDENOPTERIN HYDROBROMIDE

SMILES

InChI

CNS Activity

Approval Year

Targets

Conditions

Cmax

AUC

T1/2

Funbound

Doses

AEs

Overview

OverviewOther

Drug as perpetrator​

Drug as victim

Tox targets

PubMed

Patents

Sample Use Guides

C_max

T_1/2

F_unbound

Drug as perpetrator