Discovery of neuroprotective agents that inhibit human prolyl hydroxylase PHD2

Bioorg Med Chem. 2021 May 15:38:116115. doi: 10.1016/j.bmc.2021.116115. Epub 2021 Mar 24.

Abstract

Prolyl hydroxylase (PHD) enzymes play a critical role in the cellular responses to hypoxia through their regulation of the hypoxia inducible factor α (HIF-α) transcription factors. PHD inhibitors show promise for the treatment of diseases including anaemia, cardiovascular disease and stroke. In this work, a pharmacophore-based virtual high throughput screen was used to identify novel potential inhibitors of human PHD2. Two moderately potent new inhibitors were discovered, with IC50 values of 4 μM and 23 μM respectively. Cell-based studies demonstrate that these compounds exhibit protective activity in neuroblastoma cells, suggesting that they have the potential to be developed into clinically useful neuroprotective agents.

Keywords: Docking; Hypoxia inducible factor; Neuroprotection; Oxidative stress; Prolyl hydroxylase; Virtual screen.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Survival / drug effects
  • Dose-Response Relationship, Drug
  • Drug Discovery*
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Humans
  • Hypoxia-Inducible Factor-Proline Dioxygenases / antagonists & inhibitors*
  • Hypoxia-Inducible Factor-Proline Dioxygenases / metabolism
  • Molecular Structure
  • Neuroprotective Agents / chemical synthesis
  • Neuroprotective Agents / chemistry
  • Neuroprotective Agents / pharmacology*
  • Structure-Activity Relationship
  • Tumor Cells, Cultured

Substances

  • Enzyme Inhibitors
  • Neuroprotective Agents
  • EGLN1 protein, human
  • Hypoxia-Inducible Factor-Proline Dioxygenases