HTS followed by NMR based counterscreening. Discovery and optimization of pyrimidones as reversible and competitive inhibitors of xanthine oxidase

Bioorg Med Chem Lett. 2014 Mar 1;24(5):1315-21. doi: 10.1016/j.bmcl.2014.01.050. Epub 2014 Jan 28.

Abstract

The identification of novel, non-purine based inhibitors of xanthine oxidase is described. After a high-throughput screening campaign, an NMR based counterscreen was used to distinguish actives, which interact with XO in a reversible manner, from assay artefacts. This approach identified pyrimidone 1 as a reversible and competitive inhibitor with good lead-like properties. A hit to lead campaign gave compound 41, a nanomolar inhibitor of hXO with efficacy in the hyperuricemic rat model after oral dosing.

Keywords: High-throughput screening; Hit-to-lead; Non-purine XO inhibitors; Pyrimidone; Xanthine oxidase.

MeSH terms

  • Animals
  • Binding Sites
  • Drug Evaluation, Preclinical
  • Enzyme Activation / drug effects
  • Enzyme Inhibitors / chemistry*
  • Enzyme Inhibitors / pharmacokinetics
  • Enzyme Inhibitors / pharmacology*
  • Enzyme Inhibitors / therapeutic use
  • Gout Suppressants / chemistry
  • Gout Suppressants / pharmacokinetics
  • Gout Suppressants / pharmacology
  • Gout Suppressants / therapeutic use
  • Half-Life
  • High-Throughput Screening Assays
  • Hyperuricemia / drug therapy
  • Magnetic Resonance Spectroscopy
  • Molecular Docking Simulation
  • Protein Binding
  • Protein Structure, Tertiary
  • Pyrimidinones / chemistry*
  • Pyrimidinones / pharmacokinetics
  • Pyrimidinones / pharmacology*
  • Pyrimidinones / therapeutic use
  • Rats
  • Structure-Activity Relationship
  • Xanthine Oxidase / antagonists & inhibitors*
  • Xanthine Oxidase / metabolism

Substances

  • Enzyme Inhibitors
  • Gout Suppressants
  • Pyrimidinones
  • Xanthine Oxidase