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Inhibition of para ‐Hydroxyphenylpyruvate Dioxygenase by Analogues of the Herbicide Nitisinone As a Strategy to Decrease Homogentisic Acid Levels, the Causative Agent of Alkaptonuria
Author(s) -
Laschi Marcella,
Bernardini Giulia,
Dreassi Elena,
Millucci Lia,
Geminiani Michela,
Braconi Daniela,
Marzocchi Barbara,
Botta Maurizio,
Manetti Fabrizio,
Santucci Annalisa
Publication year - 2016
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201500578
Subject(s) - homogentisic acid , alkaptonuria , tyrosinemia , ochronosis , tyrosine , chemistry , pharmacology , transamination , biochemistry , medicine , amino acid , surgery
Alkaptonuria (AKU) is a rare multisystem metabolic disease caused by deficient activity of homogentisate 1,2‐dioxygenase (HGD), which leads to the accumulation of homogentisic acid (HGA). Currently, there is no treatment for AKU. The sole drug with some beneficial effects is the herbicide nitisinone ( 1 ), an inhibitor of p ‐hydroxyphenylpyruvate dioxygenase (4‐HPPD). 1 has been used as a life‐saving drug in infants with type I tyrosinemia despite severe side effects due to the buildup of tyrosine. Four clinical trials of nitisinone to treat AKU have shown that 1 consistently decreases HGA levels, but also caused the accumulation of tyrosine in blood serum. Moreover, the human preclinical toxicological data for 1 are incomplete. In this work, we performed pharmacodynamics and toxicological evaluations of 1 , providing the first report of LD 50 values in human cells. Intracellular tyrosinemia was also evaluated. Three additional 4‐HPPD inhibitors with a more favorable profile than that of 1 in terms of IC 50 , LD 50 , and tyrosine accumulation were also identified among commercially available compounds. These may be promising starting points for the development of new therapeutic strategies for the treatment of AKU.