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Identification
NameNitisinone
Accession NumberDB00348  (APRD01141)
TypeSmall Molecule
GroupsApproved, Investigational
Description

Nitisinone is a synthetic reversible inhibitor of 4-hydroxyphenylpyruvate dioxygenase. It is used in the treatment of hereditary tyrosinemia type 1. It is sold under the brand name Orfadin. [Wikipedia]

Structure
Thumb
Synonyms
2-(alpha,alpha,alpha-Trifluoro-2-nitro-P-tuluoyl)-1,3-cyclohexanedione
Nitisinona
Nitisinonum
Orfadin
External Identifiers Not Available
Approved Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
Orfadincapsule2 mg/1oralSWEDISH ORPHAN BIOVITRUM AB (PUBL)2014-04-01Not applicableUs
Orfadincapsule10 mg/1oralSWEDISH ORPHAN BIOVITRUM AB (PUBL)2014-04-01Not applicableUs
Orfadincapsule5 mg/1oralSWEDISH ORPHAN BIOVITRUM AB (PUBL)2014-04-01Not applicableUs
Approved Generic Prescription ProductsNot Available
Approved Over the Counter ProductsNot Available
Unapproved/Other Products Not Available
International BrandsNot Available
Brand mixturesNot Available
SaltsNot Available
Categories
UNIIK5BN214699
CAS number104206-65-7
WeightAverage: 329.2281
Monoisotopic: 329.05110705
Chemical FormulaC14H10F3NO5
InChI KeyInChIKey=OUBCNLGXQFSTLU-UHFFFAOYSA-N
InChI
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
IUPAC Name
2-[2-nitro-4-(trifluoromethyl)benzoyl]cyclohexane-1,3-dione
SMILES
[O-][N+](=O)C1=C(C=CC(=C1)C(F)(F)F)C(=O)C1C(=O)CCCC1=O
Taxonomy
DescriptionThis compound belongs to the class of organic compounds known as nitrobenzenes. These are compounds containing a nitrobenzene moiety, which consists of a benzene ring with a carbon bearing a nitro group.
KingdomOrganic compounds
Super ClassBenzenoids
ClassBenzene and substituted derivatives
Sub ClassNitrobenzenes
Direct ParentNitrobenzenes
Alternative Parents
Substituents
  • Nitrobenzene
  • Acetophenone
  • Aryl alkyl ketone
  • Aryl ketone
  • Benzoyl
  • 1,3-diketone
  • Cyclohexanone
  • 1,3-dicarbonyl compound
  • Organic nitro compound
  • Cyclic ketone
  • Organic nitrite
  • C-nitro compound
  • Ketone
  • Organic 1,3-dipolar compound
  • Propargyl-type 1,3-dipolar organic compound
  • Allyl-type 1,3-dipolar organic compound
  • Organic oxoazanium
  • Hydrocarbon derivative
  • Organic salt
  • Organooxygen compound
  • Organonitrogen compound
  • Organofluoride
  • Organohalogen compound
  • Carbonyl group
  • Alkyl halide
  • Alkyl fluoride
  • Organic zwitterion
  • Aromatic homomonocyclic compound
Molecular FrameworkAromatic homomonocyclic compounds
External Descriptors
Pharmacology
IndicationUsed as an adjunct to dietary restriction of tyrosine and phenylalanine in the treatment of hereditary tyrosinemia type 1.
PharmacodynamicsHereditary tyrosinemia type 1 occurs due to a deficiency in fumarylacetoacetase (FAH), the final enzyme in the tyrosine catabolic pathway. Nitisinone inhibits catabolism of tyrosine by preventing the catabolic intermediates. 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.
Mechanism of actionNitisinone is a competitive inhibitor of 4-hydroxyphenyl-pyruvate dioxygenase, an enzyme upstream of fumarylacetoacetate hydrolyase (FAH) in the tyrosine catabolic pathway. By inhibiting the normal catabolism of tyrosine in patients with hereditary tyrosinemia type 1 (HT-1), nitisinone prevents the accumulation of the catabolic intermediates maleylacetoacetate and fumarylacetoacetate.
Related Articles
AbsorptionThe capsule and liquid formulations are bioequivalent in both the plasma concentration-time curve and maximum plasma concentration (Cmax).
Volume of distributionNot Available
Protein bindingNot Available
MetabolismNot Available
Route of eliminationNot Available
Half life~54 hours
ClearanceNot Available
ToxicitySide effects include elevated plasma levels of this amino acid, hepatic and liver failure.
Affected organisms
  • Humans and other mammals
PathwaysNot Available
SNP Mediated EffectsNot Available
SNP Mediated Adverse Drug ReactionsNot Available
ADMET
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption+0.9849
Blood Brain Barrier+0.87
Caco-2 permeable-0.5086
P-glycoprotein substrateNon-substrate0.8491
P-glycoprotein inhibitor IInhibitor0.7006
P-glycoprotein inhibitor IINon-inhibitor0.8517
Renal organic cation transporterNon-inhibitor0.8355
CYP450 2C9 substrateNon-substrate0.7862
CYP450 2D6 substrateNon-substrate0.8292
CYP450 3A4 substrateSubstrate0.5765
CYP450 1A2 substrateInhibitor0.5808
CYP450 2C9 inhibitorNon-inhibitor0.5566
CYP450 2D6 inhibitorNon-inhibitor0.8867
CYP450 2C19 inhibitorInhibitor0.5431
CYP450 3A4 inhibitorInhibitor0.6104
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.5347
Ames testNon AMES toxic0.5612
CarcinogenicityNon-carcinogens0.6585
BiodegradationNot ready biodegradable0.9836
Rat acute toxicity2.6075 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.6292
hERG inhibition (predictor II)Non-inhibitor0.7814
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397 )
Pharmacoeconomics
Manufacturers
  • Rare disease therapeutics inc
Packagers
Dosage forms
FormRouteStrength
Capsuleoral10 mg/1
Capsuleoral2 mg/1
Capsuleoral5 mg/1
Prices
Unit descriptionCostUnit
Orfadin 10 mg capsule308.68USD capsule
Orfadin 5 mg capsule154.34USD capsule
Orfadin 2 mg capsule61.74USD capsule
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)
US5550165 No1993-08-272013-08-27Us
US9301932 No2013-02-022033-02-02Us
Properties
StateSolid
Experimental Properties
PropertyValueSource
logP1.6Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.00811 mg/mLALOGPS
logP2.06ALOGPS
logP3.13ChemAxon
logS-4.6ALOGPS
pKa (Strongest Acidic)2.71ChemAxon
pKa (Strongest Basic)-7.3ChemAxon
Physiological Charge-1ChemAxon
Hydrogen Acceptor Count5ChemAxon
Hydrogen Donor Count0ChemAxon
Polar Surface Area97.03 Å2ChemAxon
Rotatable Bond Count4ChemAxon
Refractivity72.35 m3·mol-1ChemAxon
Polarizability26.74 Å3ChemAxon
Number of Rings2ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleYesChemAxon
Spectra
Mass Spec (NIST)Not Available
SpectraNot Available
References
Synthesis ReferenceNot Available
General ReferencesNot Available
External Links
ATC CodesA16AX04
AHFS CodesNot Available
PDB EntriesNot Available
FDA labelDownload (194 KB)
MSDSNot Available
Interactions
Drug InteractionsNo interactions found.
Food InteractionsNot Available

Targets

Kind
Protein
Organism
Human
Pharmacological action
yes
Actions
inhibitor
General Function:
Metal ion binding
Specific Function:
Key enzyme in the degradation of tyrosine.
Gene Name:
HPD
Uniprot ID:
P32754
Molecular Weight:
44934.12 Da
References
  1. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [PubMed:11752352 ]
  2. Fisher AA, Davis MW: Alkaptonuric ochronosis with aortic valve and joint replacements and femoral fracture: a case report and literature review. Clin Med Res. 2004 Nov;2(4):209-15. [PubMed:15931360 ]
  3. Yang DY: 4-Hydroxyphenylpyruvate dioxygenase as a drug discovery target. Drug News Perspect. 2003 Oct;16(8):493-6. [PubMed:14668946 ]
  4. Hanauske-Abel HM, Popowicz A, Remotti H, Newfield RS, Levy J: Tyrosinemia I, a model for human diseases mediated by 2-oxoacid-utilizing dioxygenases: hepatotoxin suppression by NTBC does not normalize hepatic collagen metabolism. J Pediatr Gastroenterol Nutr. 2002 Jul;35(1):73-8. [PubMed:12142814 ]
  5. Suwannarat P, O'Brien K, Perry MB, Sebring N, Bernardini I, Kaiser-Kupfer MI, Rubin BI, Tsilou E, Gerber LH, Gahl WA: Use of nitisinone in patients with alkaptonuria. Metabolism. 2005 Jun;54(6):719-28. [PubMed:15931605 ]
  6. Santra S, Baumann U: Experience of nitisinone for the pharmacological treatment of hereditary tyrosinaemia type 1. Expert Opin Pharmacother. 2008 May;9(7):1229-36. doi: 10.1517/14656566.9.7.1229. [PubMed:18422479 ]
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Drug created on June 13, 2005 07:24 / Updated on July 28, 2016 02:49