FIALURIDINE

Details

Stereochemistry	ABSOLUTE
Molecular Formula	C9H10FIN2O5
Molecular Weight	372.089
Optical Activity	UNSPECIFIED
Defined Stereocenters	4 / 4
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

OC[C@H]1O[C@H]([C@@H](F)[C@@H]1O)N2C=C(I)C(=O)NC2=O

InChI

InChIKey=IPVFGAYTKQKGBM-BYPJNBLXSA-N

InChI=1S/C9H10FIN2O5/c10-5-6(15)4(2-14)18-8(5)13-1-3(11)7(16)12-9(13)17/h1,4-6,8,14-15H,2H2,(H,12,16,17)/t4-,5+,6-,8-/m1/s1

HIDE SMILES / InChI

Description
Sources: https://www.ncbi.nlm.nih.gov/pubmed/8739593 | https://www.ncbi.nlm.nih.gov/pubmed/9258627 | https://www.ncbi.nlm.nih.gov/pubmed/7565947 | https://www.ncbi.nlm.nih.gov/pubmed/3015003

Fialuridine, or 1-(2-deoxy-2-fluoro-1-D-arabinofuranosyl)-5-iodouracil (FIAU) is a thymidine nucleoside analog with activity against various herpesviruses and hepatitis B virus (HBV) in vitro and in vivo. Herpes virus thymidine kinase considered to be a target of FIAU. In a Phase II study, fialuridine induced a severe toxic reaction in chronic hepatitis B patients characterized by hepatic failure, lactic acidosis, pancreatitis, neuropathy, and myopathy. These clinical manifestations led to the hypothesis that the toxicity of FIAU was mediated through mitochondrial dysfunction, possibly as a result of the inhibition of mitochondrial DNA polymerase gamma and/or incorporation of FIAU into mitochondrial DNA.

Originator

Approval Year

Targets

Primary Target	Pharmacology	Condition	Potency
DNA polymerase gamma subunit 1 2 Target ID: CHEMBL2732 Sources: https://www.ncbi.nlm.nih.gov/pubmed/8622980 \| https://www.ncbi.nlm.nih.gov/pubmed/7981224	Inhibitor 8297		0.015 µM [Ki]
Thymidine kinase 17 Target ID: CHEMBL1795127 Sources: https://www.ncbi.nlm.nih.gov/pubmed/3015003	Inhibitor 8297

Conditions

Condition	Modality	Targets	Highest Phase	Product
Hepatitis B 57 Sources: https://www.ncbi.nlm.nih.gov/pubmed/7565947 https://www.ncbi.nlm.nih.gov/pubmed/9258627	Primary		Phase II 1132	Unknown Approved Use Unknown
Herpes simplex infection 28 Sources: https://www.ncbi.nlm.nih.gov/pubmed/3015003	Primary		Phase II 1132	Unknown Approved Use Unknown

Doses

Dose	Population	Adverse events
0.25 mg/kg 2 times / day multiple, oral (max,total daily dose) Highest studied dose Dose: 0.25 mg/kg, 2 times / day Route: oral Route: multiple Dose: 0.25 mg/kg, 2 times / day Sources: https://www.ncbi.nlm.nih.gov/pubmed/7565947 Page: p.1100	unhealthy, ADULT n = 15 Health Status: unhealthy Condition: chronic hepatitis B Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 15 Sources: https://www.ncbi.nlm.nih.gov/pubmed/7565947 Page: p.1100	Disc. AE: Liver failure, Pancreatitis... Other AEs: Neuropathy... AEs leading to discontinuation/dose reduction: Liver failure (grade 5, 33.3%) Pancreatitis (grade 5, 33.3%) Lactic acidosis (grade 5, 33.3%) Pancreatitis (46.7%) Lactic acidosis (46.7%) Liver failure (46.7%) Other AEs: Neuropathy (grade 1-2, 33.3%) Sources: https://www.ncbi.nlm.nih.gov/pubmed/7565947 Page: p.1100

AEs

AE	Significance	Dose	Population
Lactic acidosis	46.7% Disc. AE	0.25 mg/kg 2 times / day multiple, oral (max,total daily dose) Highest studied dose Dose: 0.25 mg/kg, 2 times / day Route: oral Route: multiple Dose: 0.25 mg/kg, 2 times / day Sources: https://www.ncbi.nlm.nih.gov/pubmed/7565947 Page: p.1100	unhealthy, ADULT n = 15 Health Status: unhealthy Condition: chronic hepatitis B Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 15 Sources: https://www.ncbi.nlm.nih.gov/pubmed/7565947 Page: p.1100
Liver failure	46.7% Disc. AE	0.25 mg/kg 2 times / day multiple, oral (max,total daily dose) Highest studied dose Dose: 0.25 mg/kg, 2 times / day Route: oral Route: multiple Dose: 0.25 mg/kg, 2 times / day Sources: https://www.ncbi.nlm.nih.gov/pubmed/7565947 Page: p.1100	unhealthy, ADULT n = 15 Health Status: unhealthy Condition: chronic hepatitis B Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 15 Sources: https://www.ncbi.nlm.nih.gov/pubmed/7565947 Page: p.1100
Pancreatitis	46.7% Disc. AE	0.25 mg/kg 2 times / day multiple, oral (max,total daily dose) Highest studied dose Dose: 0.25 mg/kg, 2 times / day Route: oral Route: multiple Dose: 0.25 mg/kg, 2 times / day Sources: https://www.ncbi.nlm.nih.gov/pubmed/7565947 Page: p.1100	unhealthy, ADULT n = 15 Health Status: unhealthy Condition: chronic hepatitis B Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 15 Sources: https://www.ncbi.nlm.nih.gov/pubmed/7565947 Page: p.1100
Neuropathy	grade 1-2, 33.3%	0.25 mg/kg 2 times / day multiple, oral (max,total daily dose) Highest studied dose Dose: 0.25 mg/kg, 2 times / day Route: oral Route: multiple Dose: 0.25 mg/kg, 2 times / day Sources: https://www.ncbi.nlm.nih.gov/pubmed/7565947 Page: p.1100	unhealthy, ADULT n = 15 Health Status: unhealthy Condition: chronic hepatitis B Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 15 Sources: https://www.ncbi.nlm.nih.gov/pubmed/7565947 Page: p.1100
Lactic acidosis	grade 5, 33.3% Disc. AE	0.25 mg/kg 2 times / day multiple, oral (max,total daily dose) Highest studied dose Dose: 0.25 mg/kg, 2 times / day Route: oral Route: multiple Dose: 0.25 mg/kg, 2 times / day Sources: https://www.ncbi.nlm.nih.gov/pubmed/7565947 Page: p.1100	unhealthy, ADULT n = 15 Health Status: unhealthy Condition: chronic hepatitis B Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 15 Sources: https://www.ncbi.nlm.nih.gov/pubmed/7565947 Page: p.1100
Liver failure	grade 5, 33.3% Disc. AE	0.25 mg/kg 2 times / day multiple, oral (max,total daily dose) Highest studied dose Dose: 0.25 mg/kg, 2 times / day Route: oral Route: multiple Dose: 0.25 mg/kg, 2 times / day Sources: https://www.ncbi.nlm.nih.gov/pubmed/7565947 Page: p.1100	unhealthy, ADULT n = 15 Health Status: unhealthy Condition: chronic hepatitis B Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 15 Sources: https://www.ncbi.nlm.nih.gov/pubmed/7565947 Page: p.1100
Pancreatitis	grade 5, 33.3% Disc. AE	0.25 mg/kg 2 times / day multiple, oral (max,total daily dose) Highest studied dose Dose: 0.25 mg/kg, 2 times / day Route: oral Route: multiple Dose: 0.25 mg/kg, 2 times / day Sources: https://www.ncbi.nlm.nih.gov/pubmed/7565947 Page: p.1100	unhealthy, ADULT n = 15 Health Status: unhealthy Condition: chronic hepatitis B Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 15 Sources: https://www.ncbi.nlm.nih.gov/pubmed/7565947 Page: p.1100

Overview

CYP3A4	CYP2C9	CYP2D6	hERG

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
MDP1 1 BSEP 402	ENT1 3 TK2 3

Drug as perpetrator

Target	Modality	Activity	Metabolite	Clinical evidence
BSEP 403	inhibitor 3277 Sources: https://pubchem.ncbi.nlm.nih.gov/bioassay/1209455#sid=103570568	no [IC50 >1000 uM]
MDP1 1	inhibitor 3277 Sources: https://pubmed.ncbi.nlm.nih.gov/8622980/	yes [Ki 0.015 uM]	FIAU triphosphate 1

Drug as victim

Target	Modality	Activity	Metabolite	Clinical evidence
ENT1 3	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/31505000/	yes
TK2 3	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/31505000/	yes

Sourcing

Vendor/Aggregator	ID	URL
1PlusChem LLC	1P0032Z1	https://www.1pchem.com/search?query=1P0032Z1
AK Scientific	0662AC	https://aksci.com/item_detail.php?cat=0662AC
Angene	AGN-PC-0TUOQ2	http://www.angenechemical.com/productshow/AGN-PC-0TUOQ2.html
AstaTech	F12931	http://astatechinc.com/CPSResult.php?CRNO=F12931
BOC Sciences	69123-98-4	http://www.bocsci.com/description.asp?cas=69123-98-4
BioSynth	J-700174	https://www.biosynth.com/en/products/life-science/other-biochemicals/products/J-700174
BioSynth	J-700352	https://www.biosynth.com/en/products/life-science/other-biochemicals/products/J-700352
BioSynth	W-203535	https://www.biosynth.com/en/products/life-science/other-biochemicals/products/W-203535
Cayman Chemical	15867	http://www.caymanchem.com/app/template/Product.vm/catalog/15867
Fluorochem	239661	http://www.fluorochem.co.uk/Products/Product?code=239661
Hairui	HR141715	http://www.hairuichem.com/en/product/search.do?q=HR141715
KeyOrganics	AS-69583	http://www.keyorganicsinc.com/bionet/catalogsearch/result?q=AS-69583
Lab Network	LN01315972	https://labnetwork.com/frontend-app/p/#!/moleculedetails/LN01315972
MolPort	MolPort-015-163-937	https://www.molport.com/shop/molecule-link/MolPort-015-163-937
MolPort	MolPort-047-133-896	https://www.molport.com/shop/molecule-link/MolPort-047-133-896
MuseChem	R009440	https://www.musechem.com/product/R009440.html
ShangHai Biochempartner	BCP001543	http://www.biochempartner.com/search_BCP001543
Tetrahedron	TS80046	http://www.thsci.com/search.do?q=TS80046
Toronto Research Chemicals	F335000	https://www.trc-canada.com/product-detail/?CatNum=F335000
W&J PharmaChem	50C473986	http://wjpharmachem.com/new/searcht.php?keyword=50C473986
eMolecules	206905858	https://orderbb.emolecules.com/search/#?query=206905858
eMolecules	6842900	https://orderbb.emolecules.com/search/#?query=6842900
eNovation Chemicals	D592831	https://www.enovationchem.com/Products.asp?SEARCHTEXT=D592831&searchbtn.x=0&searchbtn.y=0
mcule	MCULE-2056596234	https://mcule.com/MCULE-2056596234/

PubMed

Title	Date	PubMed
Nucleosides. 110. Synthesis and antiherpes virus activity of some 2'-fluoro-2'-deoxyarabinofuranosylpyrimidine nucleosides.	1979 Jan	218006
Differential activity of potential antiviral nucleoside analogs on herpes simplex virus-induced and human cellular thymidine kinases.	1981 Sep	6272634
Efficacy and selectivity of some nucleoside analogs as anti-human cytomegalovirus agents.	1983 Oct	6316843
Comparative efficacy and selectivity of some nucleoside analogs against Epstein-Barr virus.	1985 Jun	2992367
Activity of 1-(2'-deoxy-2'-fluoro-beta-D-arabinofuranosyl)-5-iodouracil against simian varicella virus infections in African green monkeys.	1986 Jan	3729332
Activities of 1-(2-deoxy-2-fluoro-beta-D-arabinofuranosyl)-5-iodocytosine and its metabolites against herpes simplex virus types 1 and 2 in cell culture and in mice infected intracerebrally with herpes simplex virus type 2.	1986 Jan	3015003
Nucleosides. 139. Synthesis and anticytomegalovirus and antiherpes simplex virus activity of 5'-modified analogues of 2'-fluoroarabinosylpyrimidine nucleosides.	1987 Jan	3027334
2'-Fluorinated arabinonucleosides of 5-(2-haloalkyl)uracil: synthesis and antiviral activity.	1987 Jul	3037079
In vitro and in vivo antiviral activity of 2'-fluorinated arabinosides of 5-(2-haloalkyl)uracil.	1987 Jun	2821896
Multiple nuclear dots antinuclear antibodies are not specific for primary biliary cirrhosis.	1992 Jul	1319948
Use of a standardized cell culture assay to assess activities of nucleoside analogs against hepatitis B virus replication.	1992 Jul 1	1444322
The in vitro anti-hepatitis B virus activity of FIAU [1-(2'-deoxy-2'-fluoro-1-beta-D-arabinofuranosyl-5-iodo)uracil] is selective, reversible, and determined, at least in part, by the host cell.	1994 Jan	8141592
Structure-activity relationship of the affinity of 5-substituted uracil nucleoside analogues for varicella-zoster virus thymidine kinase and their activity against varicella-zoster virus.	1997 Aug	9298756
Identification of BMS-200475 as a potent and selective inhibitor of hepatitis B virus.	1997 Jul	9210663
Anti-herpesvirus activity profile of 4'-thioarabinofuranosyl purine and uracil nucleosides and activity of 1-beta-D-2'-fluoro-4'-thioarabinofuranosyl guanine and 2,6-diaminopurine against clinical isolates of human cytomegalovirus.	1998 Aug	9806489
Enhanced inhibition of orthopoxvirus replication in vitro by alkoxyalkyl esters of cidofovir and cyclic cidofovir.	2002 Apr	11897580
In vitro activity of potential anti-poxvirus agents.	2003 Jan	12615301
Specific genetic modifications of domestic animals by gene targeting and animal cloning.	2003 Nov 13	14614774
Development of radioiodinated nucleoside analogs for imaging tissue proliferation: comparisons of six 5-iodonucleosides.	2003 Oct	14499326
Anti-cowpox virus activities of certain adenosine analogs, arabinofuranosyl nucleosides, and 2'-fluoro-arabinofuranosyl nucleosides.	2004	15043161
Biodistribution, cellular uptake and DNA-incorporation of the 2'-fluoro stabilized 5-iodo-2'-deoxyuridine analog 5-iodo-(2-deoxy-2-fluoro-beta-D-arabinofuranosyl)uracil (FIAU).	2008 Sep	18432182
Myopathy and neuropathy associated with nucleos(t)ide analog therapy for hepatitis B.	2009 Oct	19665816
Effects of structural differences between radioiodine-labeled 1-(2'-fluoro-2'-deoxy-D-arabinofuranosyl)-5-iodouracil (FIAU) and 1-(2'-fluoro-2'-deoxy-d-ribofuranosyl)-5-iodouracil (FIRU) on HSV1-TK reporter gene imaging.	2010 Jun	20083410
Development of a multiparametric cell-based protocol to screen and classify the hepatotoxicity potential of drugs.	2012 May	22331495
A correlation between the in vitro drug toxicity of drugs to cell lines that express human P450s and their propensity to cause liver injury in humans.	2014 Jan	24085192

Patents

Sample Use Guides

In Vivo Use Guide

This phase 2 trial was designed to evaluate the safety and efficacy of a six-month course of fialuridine in 24 patients with chronic hepatitisB. Patients were randomly assigned to receive either 0.10 or 0.25 mg of fialuridine per kilogram of body weight per day given orally in two or three divided doses. In patients with chronic hepatitis B, treatment with fialuridine induced a severe toxic reaction characterized by hepatic failure, lactic acidosis, pancreatitis, neuropathy, and myopathy.

Route of Administration: Oral

In Vitro Use Guide

Mitochondria isolated from livers of naive rats were treated in vitro with concentrations of Fialuridine, or 1-(2-deoxy-2-fluoro-1-D-arabinofuranosyl)-5-iodouracil (FIAU) or FIAU triphosphate (FIAU-TP) ranging from 0.1 to 200 microM. A 14 or 32% decrease in mitochondrial DNA synthesis compared to controls was observed when isolated mitochondria were treated with 25 microM FIAU or FIAU-TP, respectively.

Name

Type

Language

FIALURIDINE

Official Name

English

FIALURIDINE [USAN]

Common Name

English

1-(2-DEOXY-2-FLUORO-.BETA.-D-ARABINOFURANOSYL)-5-IODOURACIL

Common Name

English

FIALURIDINE [MART.]

Common Name

English

FIALURIDINE [MI]

Common Name

English

NSC-678514

Code

English

fialuridine [INN]

Common Name

English

2,4(1H,3H)-PYRIMIDINEDIONE, 1-(2-DEOXY-2-FLUORO-.BETA.-D-ARABINOFURANOSYL)-5-IODO-

Common Name

English

Classification Tree Code System Code

FDA ORPHAN DRUG

67892