Nitisinone

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Cat Number

API104206657

CAS Number

104206-65-7

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CAS Number

104206-65-7

EINECS

691-056-0

Storage

Store at room temperature

Synonyms

Orfadin; 2-(2-nitro-4-(trifluoromethyl)benzoyl)cyclohexane-1,3-dione; nitisinona; nitisinonum; SC-0735

Molecular Formula

C14H10F3NO5

Molecular Weight

329.23

Smiles

C1CC(=O)C(C(=O)C1)C(=O)C2=C(C=C(C=C2)C(F)(F)F)[N+](=O)[O-]

Melting Point

129-131°C

Boiling Point

486.2±45.0°C at 760 mmHg (Predicted)

Relative Density

1.484±0.06 (Predicted)

General Description

Nitisinone is a synthetic small molecule with a nitrophenyl and a cyclopropyl group, belonging to the class of triketone herbicides. Its chemical structure is 2-[2-nitro-4-(trifluoromethyl)benzoyl]cyclohexane-1,3-dione. Nitisinone is a white to off-white powder, practically insoluble in water but soluble in organic solvents. It is a potent inhibitor of 4-hydroxyphenylpyruvate dioxygenase (HPPD).

Mechanism of Action

Nitisinone acts as a competitive inhibitor of the enzyme 4-hydroxyphenylpyruvate dioxygenase (HPPD), which catalyzes the second step in the catabolism of tyrosine. By blocking this enzyme, it prevents the formation of maleylacetoacetate and fumarylacetoacetate, which are precursors to the toxic metabolites that cause liver and kidney damage in hereditary tyrosinemia type 1.

Application

Nitisinone is indicated for the treatment of hereditary tyrosinemia type 1 (HT-1) in adults and children, in combination with dietary restriction of tyrosine and phenylalanine. It reduces the accumulation of toxic metabolites, improves liver function, and reduces the risk of hepatocellular carcinoma. The drug is also used for the treatment of alkaptonuria (ochronosis) and for the management of other disorders of tyrosine metabolism.

Nitisinone, combined with a low‑protein diet, has transformed the prognosis of hereditary tyrosinemia type 1 (HT‑1) by blocking tyrosine catabolism and reducing toxic metabolites. Early diagnosis via newborn screening (succinylacetone as the reliable marker) and immediate treatment prevent liver failure, renal dysfunction, rickets, neurological crises, and hepatocellular carcinoma. Side effects are rare, though reversible eye symptoms and possible neurocognitive impairment require monitoring.

Fig. 1 Degradative pathway of tyrosine. (Das AM. 2017)

References

Das AM. Clinical utility of nitisinone for the treatment of hereditary tyrosinemia type-1 (HT-1). Appl Clin Genet. 2017;10:43-48.

Nitisinone (NTBC), an FDA-approved tyrosine catabolism inhibitor, killed tsetse flies (vectors of African trypanosomiasis) when administered orally or topically, while not affecting bumblebee survival. RNAi of tyrosine aminotransferase or 4-hydroxyphenylpyruvate dioxygenase was also lethal to tsetse. Mathematical modeling suggested NTBC could reduce transmission of African trypanosomiasis in sub-Saharan Africa. This represents an environmentally friendly insecticide alternative targeting the tyrosine metabolism pathway.

Fig. 2 Metabolomic analysis of tsetse haemolymph upon NTBC treatment at different times post-bloodmeal (0, 5, and 10 hours). (Sterkel M, et al., 2021)

References

Sterkel M, et al. Repurposing the orphan drug nitisinone to control the transmission of African trypanosomiasis. PLoS Biol. 2021;19(1):e3000796.

Does Nitisinone require protection from light during long-term storage?

Yes, it is photosensitive. UV exposure can cause photodegradation and discoloration of the nitrophenyl ring. Store in light-resistant containers, preferably amber glass.

What is the recommended storage temperature for Nitisinone?

Store at controlled room temperature (15-25°C). Avoid excessive heat above 30°C, which can accelerate oxidative degradation.

Is Nitisinone stable in capsule formulations with standard excipients?

Yes, when formulated with moisture-protective packaging.

How is the impurity nitisinone N-oxide (an oxidative degradation product) monitored?

This degradation product is quantified using a stability-indicating HPLC method, ensuring it remains within ICH qualification thresholds.