Discovery of Novel, Potent Inhibitors of Hydroxy Acid Oxidase 1 (HAO1) Using DNA-Encoded Chemical Library Screening

J Med Chem. 2021 May 27;64(10):6730-6744. doi: 10.1021/acs.jmedchem.0c02271. Epub 2021 May 6.

Abstract

Inhibition of hydroxy acid oxidase 1 (HAO1) is a strategy to mitigate the accumulation of toxic oxalate that results from reduced activity of alanine-glyoxylate aminotransferase (AGXT) in primary hyperoxaluria 1 (PH1) patients. DNA-Encoded Chemical Library (DECL) screening provided two novel chemical series of potent HAO1 inhibitors, represented by compounds 3-6. Compound 5 was further optimized via various structure-activity relationship (SAR) exploration methods to 29, a compound with improved potency and absorption, distribution, metabolism, and excretion (ADME)/pharmacokinetic (PK) properties. Since carboxylic acid-containing compounds are often poorly permeable and have potential active glucuronide metabolites, we undertook a brief, initial exploration of acid replacements with the aim of identifying non-acid-containing HAO1 inhibitors. Structure-based drug design initiated with Compound 5 led to the identification of a nonacid inhibitor of HAO1, 31, which has weaker potency and increased permeability.

MeSH terms

  • Alcohol Oxidoreductases / antagonists & inhibitors*
  • Alcohol Oxidoreductases / metabolism
  • Animals
  • Binding Sites
  • Crystallography, X-Ray
  • DNA / chemistry*
  • DNA / metabolism
  • Drug Design
  • Half-Life
  • Humans
  • Hyperoxaluria, Primary / metabolism
  • Hyperoxaluria, Primary / pathology
  • Indoles / chemistry
  • Indoles / metabolism
  • Male
  • Mice
  • Molecular Docking Simulation
  • Small Molecule Libraries / chemistry*
  • Small Molecule Libraries / metabolism
  • Structure-Activity Relationship
  • Thiazoles / chemistry
  • Thiazoles / metabolism
  • Transaminases / genetics
  • Transaminases / metabolism

Substances

  • Indoles
  • Small Molecule Libraries
  • Thiazoles
  • DNA
  • Alcohol Oxidoreductases
  • HAO1 protein, human
  • Transaminases
  • Alanine-glyoxylate transaminase