Treatment of Alkaptonuria and Tyrosinemia type 1
The invention relates to triketones compounds for their use in the prevention and treatment of a disease characterized by accumulation of homogentisic acid (HGA) or succinyl acetoacetate and succinylacetone. The invention also relates to compositions comprising such compounds.
Alkaptonuria (AKU) is a rare genetic disease caused by an accumulation and oxydation of homogentisic acid (HGA) due to insufficient activity of homogentisate 1,2-dioxygenase (HGD) involved in tyrosine catabolism. The herbicide nitisinone (compound 1) is a potent inhibitor of both human and rat 4-hydroxyphenylpyruvate dioxygenase (4-HPPD) which catalyses the transformation of the 4-hydroxyphenylpyruvate (HPP) to HGA. Approved by the FDA “in exceptional circumstances” as a life-saver in the rare paediatric hereditary disease tyrosinemia type 1 (HT1), the use of compound 1 is linked to severe side effects. Recent clinical trials confirmed that compound 1 consistently reduces HGA levels in both plasma and urine, albeit correlated with tyrosine accumulation in plasma. Alternative 4-HPPD inhibitors for AKU and HT1 treatment that reduce HGA accumulation while minimizing tyrosinemia are therefore needed.
- Rare genetic diseases;
- Novel treatment of alkaptonuria;
- Novel treatment of type 1 tyrosinemia;
- Pharmaceutical composition.
- Novel alternative nitisinone (NTBC) compounds;
- Increased 4-HPPD inhibition;
- Lower cytotoxicity.