Salicylic Acid Derivatives Inhibit Oxalate Production in Mouse Hepatocytes with Primary Hyperoxaluria Type 1

J Med Chem. 2018 Aug 23;61(16):7144-7167. doi: 10.1021/acs.jmedchem.8b00399. Epub 2018 Aug 6.

Abstract

Primary hyperoxaluria type 1 (PH1) is a rare life-threatening genetic disease related to glyoxylate metabolism and characterized by accumulation of calcium oxalate crystals. Current therapies involve hepatic and/or renal transplantation, procedures that have significant morbidity and mortality and require long-term immunosuppression. Thus, a pharmacological treatment is urgently needed. We introduce here an unprecedented activity of salicylic acid derivatives as agents capable of decreasing oxalate output in hyperoxaluric hepatocytes at the low micromolar range, which means a potential use in the treatment of PH1. Though correlation of this phenotypic activity with glycolate oxidase (GO) inhibition is still to be verified, most of the salicylic acids described here are GO inhibitors with IC50 values down to 3 μM. Binding mode of salicylic acids inside GO has been studied using in silico methods, and preliminary structure-activity relationships have been established. The drug-like structure and ease of synthesis of our compounds make them promising hits for structural optimization.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alcohol Oxidoreductases / antagonists & inhibitors*
  • Alcohol Oxidoreductases / chemistry
  • Alcohol Oxidoreductases / metabolism
  • Animals
  • Cells, Cultured
  • Computer Simulation
  • Drug Design
  • Hepatocytes / drug effects*
  • Hepatocytes / metabolism
  • Hepatocytes / pathology
  • Humans
  • Hyperoxaluria, Primary / drug therapy*
  • Hyperoxaluria, Primary / metabolism
  • Male
  • Mice, Inbred C57BL
  • Mice, Mutant Strains
  • Molecular Docking Simulation
  • Oxalates / metabolism*
  • Salicylates / chemistry*
  • Salicylates / metabolism
  • Salicylates / pharmacology
  • Structure-Activity Relationship
  • Transaminases / genetics
  • Transaminases / metabolism

Substances

  • Oxalates
  • Salicylates
  • Alcohol Oxidoreductases
  • glycollate oxidase
  • Transaminases
  • Alanine-glyoxylate transaminase

Supplementary concepts

  • Primary hyperoxaluria type 1