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Details

Stereochemistry ACHIRAL
Molecular Formula C14H10F3NO5
Molecular Weight 329.2286
Optical Activity NONE
Defined Stereocenters 0 / 0
E/Z Centers 0
Charge 0

SHOW SMILES / InChI
Structure of NITISINONE

SMILES

C1CC(=O)C(C(=O)C1)C(=O)c2ccc(cc2N(=O)=O)C(F)(F)F

InChI

InChIKey=OUBCNLGXQFSTLU-UHFFFAOYSA-N
InChI=1S/C14H10F3NO5/c15-14(16,17)7-4-5-8(9(6-7)18(22)23)13(21)12-10(19)2-1-3-11(12)20/h4-6,12H,1-3H2

HIDE SMILES / InChI

Description
Curator's Comment:: Description was created based on several sources, including https://www.ncbi.nlm.nih.gov/pubmed/25266991 https://www.ncbi.nlm.nih.gov/pubmed/25266991

Nitisinone, 2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione (NTBC) is a triketone with herbicidal activity. Orfadin® capsules contain nitisinone used in the treatment of hereditary tyrosinemia type 1 (HT-1). Nitisinone is a competitive inhibitor of 4-hydroxyphenyl-pyruvate dioxygenase, an enzyme upstream of fumarylacetoacetase in the tyrosine catabolic pathway. By inhibiting the normal catabolism of tyrosine in patients with HT-1, nitisinone prevents the accumulation of the catabolic intermediates maleylacetoacetate and fumarylacetoacetate. In patients with HT-1, these catabolic intermediates are converted to the toxic metabolites succinylacetone and succinylacetoacetate, which are responsible for the observed liver and kidney toxicity. Succinylacetone can also inhibit the porphyrin synthesis pathway leading to the accumulation of 5-aminolevulinate, a neurotoxin responsible for the porphyric crises characteristic of HT-1. Zeneca Agrochemicals and Zeneca Pharmaceuticals made NTBC available for clinical use and, with the approval of the Swedish Medical Products Agency, a seriously ill child with an acute form of tyrosinaemia type 1 was successfully treated in February 1991. Nitisinone is investigated as a potential treatment for other disorders of tyrosine metabolism including alkaptonuria.

Approval Year

Targets

Targets

Primary TargetPharmacologyConditionPotency
5.0 nM [IC50]
Conditions

Conditions

ConditionModalityTargetsHighest PhaseProduct
Primary
ORFADIN

Approved Use

ORFADIN® capsules (nitisinone) are indicated as an adjunct to dietary restriction of tyrosine and phenylalanine in the treatment of patients with hereditary tyrosinemia type 1 (HT-1). ORFADIN is a synthetic reversible inhibitor of 4-hydroxyphenylpyruvate dioxygenase indicated for use as an adjunct to dietary restriction of tyrosine and phenylalanine in the treatment of hereditary tyrosinemia type 1 (HT-1). (1)

Launch Date

1.01131197E12
Cmax

Cmax

ValueDoseCo-administeredAnalytePopulation
1278 ng/mL
10 mg single, oral
dose: 10 mg
route of administration: Oral
experiment type: SINGLE
co-administered:
NITISINONE plasma
Homo sapiens
population: HEALTHY
age: UNKNOWN
sex: UNKNOWN
food status: FASTED
AUC

AUC

ValueDoseCo-administeredAnalytePopulation
77874 ng × h/mL
10 mg single, oral
dose: 10 mg
route of administration: Oral
experiment type: SINGLE
co-administered:
NITISINONE plasma
Homo sapiens
population: HEALTHY
age: UNKNOWN
sex: UNKNOWN
food status: FASTED
Doses

Doses

DosePopulationAdverse events​
80 mg single, oral
Highest studied dose
Dose: 80 mg
Route: oral
Route: single
Dose: 80 mg
Sources:
healthy, 18-55 years
Health Status: healthy
Age Group: 18-55 years
Sex: M+F
Sources:
Overview

Overview

Drug as perpetrator​

Drug as perpetrator​

TargetModalityActivityMetaboliteClinical evidence
inconclusive
inconclusive
likely
no
no
no
no
no
no
no
no
no
no
no
weak
yes
yes
Drug as victim

Drug as victim

TargetModalityActivityMetaboliteClinical evidence
minor
PubMed

PubMed

TitleDatePubMed
Pharmacokinetics and pharmacodynamics of NTBC (2-(2-nitro-4-fluoromethylbenzoyl)-1,3-cyclohexanedione) and mesotrione, inhibitors of 4-hydroxyphenyl pyruvate dioxygenase (HPPD) following a single dose to healthy male volunteers.
2001 Aug
[Evolution of a case of tyrosinemia type I treated with NTBC].
2001 Mar
Nitisinone. Ntbc, Orfadin.
2002
Corneal opacities associated with NTBC treatment.
2002 Aug
Long-term therapy with NTBC and tyrosine-restricted diet in a murine model of hereditary tyrosinemia type I.
2002 Jan
Drug to treat rare pediatric liver disease.
2002 Mar-Apr
Ophthalmic follow-up of patients with tyrosinaemia type I on NTBC.
2003
The role of mode of action studies in extrapolating to human risks in toxicology.
2003 Apr 11
Pharmacological rescue of the 14CoS/14CoS mouse: hepatocyte apoptosis is likely caused by endogenous oxidative stress.
2003 Aug 15
Extensive changes in liver gene expression induced by hereditary tyrosinemia type I are not normalized by treatment with 2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione (NTBC).
2003 Dec
4-Hydroxyphenylpyruvate dioxygenase as a drug discovery target.
2003 Oct
Interaction of (4-hydroxyphenyl)pyruvate dioxygenase with the specific inhibitor 2-[2-nitro-4-(trifluoromethyl)benzoyl]-1,3-cyclohexanedione.
2003 Sep 2
Liquid chromatography-tandem mass spectrometry method for the simultaneous determination of delta-ALA, tyrosine and creatinine in biological fluids.
2004 Dec
Structure of the ferrous form of (4-hydroxyphenyl)pyruvate dioxygenase from Streptomyces avermitilis in complex with the therapeutic herbicide, NTBC.
2004 Jun 1
Renal proximal tubular cells acquire resistance to cell death stimuli in mice with hereditary tyrosinemia type 1.
2004 Sep
D-serine-induced nephrotoxicity: possible interaction with tyrosine metabolism.
2004 Sep 1
Successful treatment of severe cardiomyopathy with NTBC in a child with tyrosinaemia type I.
2005
Transcriptome analysis of Paracoccidioides brasiliensis cells undergoing mycelium-to-yeast transition.
2005 Dec
Use of nitisinone in patients with alkaptonuria.
2005 Jun
New developments in ochronosis: review of the literature.
2005 Mar
Current strategies for the treatment of hereditary tyrosinemia type I.
2006
Response of metastatic recurrent neuroblastoma to nitisinone: a modulator of tyrosine metabolism.
2006 Apr
Tyrosinemia type I treated by NTBC: how does AFP predict liver cancer?
2006 Dec
Gateways to clinical trials.
2006 Mar
Harnessing a high cargo-capacity transposon for genetic applications in vertebrates.
2006 Nov 10
[New drugs; nitisinone].
2006 Nov 18
Messenger RNA as a source of transposase for sleeping beauty transposon-mediated correction of hereditary tyrosinemia type I.
2007 Jul
Identification of 2-[2-nitro-4-(trifluoromethyl)benzoyl]- cyclohexane-1,3-dione metabolites in urine of patients suffering from tyrosinemia type I with the use of 1H and 19F NMR spectroscopy.
2008
Activation of nuclear factor E2-related factor 2 in hereditary tyrosinemia type 1 and its role in survival and tumor development.
2008 Aug
Hepatic stress in hereditary tyrosinemia type 1 (HT1) activates the AKT survival pathway in the fah-/- knockout mice model.
2008 Feb
Rescue from neonatal death in the murine model of hereditary tyrosinemia by glutathione monoethylester and vitamin C treatment.
2008 Mar
Alkaptonuria diagnosed in a 4-month-old baby girl: a case report.
2008 Nov 13
A novel mutation causing mild, atypical fumarylacetoacetase deficiency (Tyrosinemia type I): a case report.
2009 Dec 15
Persistent coagulopathy during Escherichia coli sepsis in a previously healthy infant revealed undiagnosed tyrosinaemia type 1.
2010 Dec 29
Tyrosinemia type 1: metastatic hepatoblastoma with a favorable outcome.
2010 Jul
Identification of NTBC metabolites in urine from patients with hereditary tyrosinemia type 1 using two different mass spectrometric platforms: triple stage quadrupole and LTQ-Orbitrap.
2010 Mar
Patents

Sample Use Guides

Treatment with nitisinone should be initiated by a physician experienced in the treatment of hereditary tyrosinemia type 1. The dose of nitisinone should be adjusted in each patient. The recommended initial dose is 1 mg/kg/day divided for morning and evening administration. Since an effect of food is unknown, nitisinone should be taken at least one hour before a meal. Because of the long halflife of nitisinone, the total dose may be split unevenly as convenient in order to limit the total number of capsules given at each administration. A nutritionist skilled in managing children with inborn errors of metabolism should be employed to design a low-protein diet deficient in tyrosine and phenylalanine. For young children, capsules may be opened and the contents suspended in a small amount of water, formula, or apple sauce immediately before use.
Route of Administration: Oral
There is currently no literature surrounding the use of nitisinone in human in vitro models, or its effect on chondrocytes or osteoblast like cells. Nitisinone (1nM - uM) does not appear detrimental to cell viability of chondrocytes or osteoblast-like cells.
Name Type Language
NITISINONE
EMA EPAR   INN   JAN   MART.   MI   ORANGE BOOK   USAN   VANDF   WHO-DD  
INN   USAN  
Official Name English
NITISINONE [VANDF]
Common Name English
SC-0735
Code English
NITISINONE [JAN]
Common Name English
2-(.ALPHA.,.ALPHA.,.ALPHA.-TRIFLUORO-2-NITRO-P-TULUOYL)-1,3-CYCLOHEXANEDIONE
Common Name English
NITYR
Brand Name English
ORFADIN
Brand Name English
NITISINONE [MI]
Common Name English
NITISINONE [ORANGE BOOK]
Common Name English
NITISINONE [WHO-DD]
Common Name English
1,3-CYCLOHEXANEDIONE, 2-(2-NITRO-4-(TRIFLUOROMETHYL)BENZOYL)-
Systematic Name English
NITISINONE [INN]
Common Name English
NITISINONE [MART.]
Common Name English
NTBC
Common Name English
NITISINONE [EMA EPAR]
Common Name English
NITISINONE [USAN]
Common Name English
Classification Tree Code System Code
WHO-VATC QA16AX04
Created by admin on Sat Jun 26 06:20:55 UTC 2021 , Edited by admin on Sat Jun 26 06:20:55 UTC 2021
EPA PESTICIDE CODE 12802
Created by admin on Sat Jun 26 06:20:55 UTC 2021 , Edited by admin on Sat Jun 26 06:20:55 UTC 2021
WHO-ATC A16AX04
Created by admin on Sat Jun 26 06:20:54 UTC 2021 , Edited by admin on Sat Jun 26 06:20:54 UTC 2021
NCI_THESAURUS C471
Created by admin on Sat Jun 26 06:20:55 UTC 2021 , Edited by admin on Sat Jun 26 06:20:55 UTC 2021
FDA ORPHAN DRUG 148701
Created by admin on Sat Jun 26 06:20:55 UTC 2021 , Edited by admin on Sat Jun 26 06:20:55 UTC 2021
NDF-RT N0000175808
Created by admin on Sat Jun 26 06:20:55 UTC 2021 , Edited by admin on Sat Jun 26 06:20:55 UTC 2021
NDF-RT N0000175809
Created by admin on Sat Jun 26 06:20:55 UTC 2021 , Edited by admin on Sat Jun 26 06:20:55 UTC 2021
EU-Orphan Drug EU/3/00/012
Created by admin on Sat Jun 26 06:20:55 UTC 2021 , Edited by admin on Sat Jun 26 06:20:55 UTC 2021
FDA ORPHAN DRUG 89095
Created by admin on Sat Jun 26 06:20:55 UTC 2021 , Edited by admin on Sat Jun 26 06:20:55 UTC 2021
EMA ASSESSMENT REPORTS ORFADIN (AUTHORIZED: TYROSINEMIAS)
Created by admin on Sat Jun 26 06:20:54 UTC 2021 , Edited by admin on Sat Jun 26 06:20:54 UTC 2021
Code System Code Type Description
CAS
104206-65-7
Created by admin on Sat Jun 26 06:20:54 UTC 2021 , Edited by admin on Sat Jun 26 06:20:54 UTC 2021
PRIMARY
DRUG BANK
DB00348
Created by admin on Sat Jun 26 06:20:54 UTC 2021 , Edited by admin on Sat Jun 26 06:20:54 UTC 2021
PRIMARY
IUPHAR
6834
Created by admin on Sat Jun 26 06:20:55 UTC 2021 , Edited by admin on Sat Jun 26 06:20:55 UTC 2021
PRIMARY
JAPANESE REVIEW
ORFADIN
Created by admin on Sat Jun 26 06:20:55 UTC 2021 , Edited by admin on Sat Jun 26 06:20:55 UTC 2021
PRIMARY APPROVED DECEMBER 2014
RXCUI
61805
Created by admin on Sat Jun 26 06:20:55 UTC 2021 , Edited by admin on Sat Jun 26 06:20:55 UTC 2021
PRIMARY RxNorm
INN
7720
Created by admin on Sat Jun 26 06:20:55 UTC 2021 , Edited by admin on Sat Jun 26 06:20:55 UTC 2021
PRIMARY
EPA CompTox
104206-65-7
Created by admin on Sat Jun 26 06:20:54 UTC 2021 , Edited by admin on Sat Jun 26 06:20:54 UTC 2021
PRIMARY
MERCK INDEX
M7926
Created by admin on Sat Jun 26 06:20:55 UTC 2021 , Edited by admin on Sat Jun 26 06:20:55 UTC 2021
PRIMARY Merck Index
MESH
C077073
Created by admin on Sat Jun 26 06:20:55 UTC 2021 , Edited by admin on Sat Jun 26 06:20:55 UTC 2021
PRIMARY
DRUG CENTRAL
1944
Created by admin on Sat Jun 26 06:20:54 UTC 2021 , Edited by admin on Sat Jun 26 06:20:54 UTC 2021
PRIMARY
EVMPD
SUB09313MIG
Created by admin on Sat Jun 26 06:20:54 UTC 2021 , Edited by admin on Sat Jun 26 06:20:54 UTC 2021
PRIMARY
ChEMBL
CHEMBL1337
Created by admin on Sat Jun 26 06:20:54 UTC 2021 , Edited by admin on Sat Jun 26 06:20:54 UTC 2021
PRIMARY
FDA UNII
K5BN214699
Created by admin on Sat Jun 26 06:20:55 UTC 2021 , Edited by admin on Sat Jun 26 06:20:55 UTC 2021
PRIMARY
PUBCHEM
115355
Created by admin on Sat Jun 26 06:20:55 UTC 2021 , Edited by admin on Sat Jun 26 06:20:55 UTC 2021
PRIMARY
NCI_THESAURUS
C61862
Created by admin on Sat Jun 26 06:20:55 UTC 2021 , Edited by admin on Sat Jun 26 06:20:55 UTC 2021
PRIMARY