Inhibition of para-Hydroxyphenylpyruvate Dioxygenase by Analogues of the Herbicide Nitisinone As a Strategy to Decrease Homogentisic Acid Levels, the Causative Agent of Alkaptonuria.

Abstract

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 LD50 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 IC50, LD50, 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.

• Authors: Marcella Laschi, Giulia Bernardini, Elena Dreassi, Lia Millucci, Michela Geminiani, Daniela Braconi, Barbara Marzocchi, Maurizio Botta, Fabrizio Manetti, Annalisa Santucci
• Journal: ChemMedChem (ChemMedChem) Vol. 11 Issue 7 Pg. 674-8 (Apr 05 2016) ISSN: 1860-7187 [Electronic] Germany
• PMID: 26947423 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Chemical References

• Cyclohexanones
• Herbicides
• Nitrobenzoates
• 4-Hydroxyphenylpyruvate Dioxygenase
• nitisinone
• Homogentisic Acid

Topics

• 4-Hydroxyphenylpyruvate Dioxygenase (antagonists & inhibitors, metabolism)
• Alkaptonuria (drug therapy, metabolism)
• Animals
• Cell Survival (drug effects)
• Cyclohexanones (chemical synthesis, chemistry, pharmacology)
• Dose-Response Relationship, Drug
• Herbicides (chemical synthesis, chemistry, pharmacology)
• Homogentisic Acid (metabolism)
• Humans
• Male
• Molecular Structure
• Nitrobenzoates (chemical synthesis, chemistry, pharmacology)
• Rats
• Rats, Wistar
• Structure-Activity Relationship