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Identification
Name Nitisinone
Accession Number DB00348 (APRD01141)
Type small molecule
Groups approved
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
Download: MOL | SDF | SMILES | InChI
Display: 2D Structure | 3D Structure
Synonyms Not Available
Synonyms Not Available
Salts Not Available
Brand names
Name Company
Orfadin
Brand mixtures Not Available
Categories
  • Enzyme Inhibitors
CAS number 104206-65-7
Weight Average: 329.2281
Monoisotopic: 329.05110705
Chemical Formula C14H10F3NO5
InChI Key InChIKey=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
Plain Text
IUPAC Name
2-{[2-nitro-4-(trifluoromethyl)phenyl]carbonyl}cyclohexane-1,3-dione
SMILES
[O-][N+](=O)C1=C(C=CC(=C1)C(F)(F)F)C(=O)C1C(=O)CCCC1=O
Plain Text
Mass Spec Not Available
Taxonomy
Kingdom Organic
Classes
  • Nitrobenzenes
  • Benzoyl Derivatives
  • Acetophenones and Derivatives
Substructures
  • Nitrobenzenes
  • Oxoazaniums
  • Halogen Derivatives
  • Benzene and Derivatives
  • Nitro compounds
  • Aromatic compounds
  • Benzoyl Derivatives
  • Acetophenones and Derivatives
  • Anilines
  • Ketones
Pharmacology
Indication Used as an adjunct to dietary restriction of tyrosine and phenylalanine in the treatment of hereditary tyrosinemia type 1.
Pharmacodynamics Hereditary 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 action Nitisinone 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.
Absorption The capsule and liquid formulations are bioequivalent in both the plasma concentration-time curve and maximum plasma concentration (Cmax).
Volume of distribution Not Available
Protein binding Not Available
Metabolism Not Available
Route of elimination Not Available
Half life ~54 hours
Clearance Not Available
Toxicity Side effects include elevated plasma levels of this amino acid, hepatic and liver failure.
Affected organisms
  • Humans and other mammals
Pathways Not Available
Pharmacoeconomics
Manufacturers
  • Rare disease therapeutics inc
Packagers
Dosage forms
Form Route Strength
Capsule Oral
Prices
Unit description Cost Unit
Orfadin 10 mg capsule 308.68 USD capsule
Orfadin 5 mg capsule 154.34 USD capsule
Orfadin 2 mg capsule 61.74 USD capsule
Patents
Country Patent Number Approved Expires (estimated)
United States 5550165 1993-08-27 2013-08-27
Properties
State solid
Melting point Not Available
Experimental Properties
Property Value Source
logP 1.6 PhysProp
Predicted Properties
Property Value Source
water solubility 8.11e-03 g/l ALOGPS
logP 2.06 ALOGPS
logP 3.13 ChemAxon Molconvert
logS -4.6 ALOGPS
pKa 0 ChemAxon Molconvert
hydrogen acceptor count 5 ChemAxon Molconvert
hydrogen donor count 0 ChemAxon Molconvert
polar surface area 97.03 ChemAxon Molconvert
rotatable bond count 4 ChemAxon Molconvert
refractivity 72.35 ChemAxon Molconvert
polarizability 26.74 ChemAxon Molconvert
References
Synthesis Reference Not Available
General Reference Not Available
External Links
Resource Link
PubChem Compound 115355 Link_out
PubChem Substance 46507380 Link_out
ChemSpider 103195 Link_out
ChEBI 50378 Link_out
ChEMBL 50378 Link_out
Therapeutic Targets Database DAP000774 Link_out
PharmGKB PA10147 Link_out
RxList http://www.rxlist.com/cgi/generic/orfadin.htm Link_out
Drugs.com http://www.drugs.com/cdi/nitisinone.html Link_out
Wikipedia http://en.wikipedia.org/wiki/Nitisinone Link_out
ATC Codes
  • A16AX04
AHFS Codes Not Available
PDB Entries Not Available
FDA label show (194 KB)
MSDS Not Available
Interactions
Drug Interactions Searched, but no interactions found.
Food Interactions Not Available
Targets

1. 4-hydroxyphenylpyruvate dioxygenase

Pharmacological action: yes
Actions: inhibitor
Organism class: human
UniProt ID: P32754 Link_out
Gene: HPD Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. Pubmed
  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
  3. Yang DY: 4-Hydroxyphenylpyruvate dioxygenase as a drug discovery target. Drug News Perspect. 2003 Oct;16(8):493-6. Pubmed
  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
  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# 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. Pubmed
Comments
Drug created on June 13, 2005 07:24 / Updated on February 14, 2012 11:41