Structure-Activity Relationship and Crystallographic Studies on 4-Hydroxypyrimidine HIF Prolyl Hydroxylase Domain Inhibitors

ChemMedChem. 2020 Feb 5;15(3):270-273. doi: 10.1002/cmdc.201900557. Epub 2019 Dec 3.

Abstract

The 2-oxoglutarate-dependent hypoxia inducible factor prolyl hydroxylases (PHDs) are targets for treatment of a variety of diseases including anaemia. One PHD inhibitor is approved for use for the treatment of renal anaemia and others are in late stage clinical trials. The number of reported templates for PHD inhibition is limited. We report structure-activity relationship and crystallographic studies on a promising class of 4-hydroxypyrimidine-containing PHD inhibitors.

Keywords: anaemia; hypoxia; prolyl hydroxylases; structure-activity relationships.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Crystallography, X-Ray
  • Dose-Response Relationship, Drug
  • Humans
  • Hypoxia-Inducible Factor-Proline Dioxygenases / antagonists & inhibitors*
  • Hypoxia-Inducible Factor-Proline Dioxygenases / metabolism
  • Models, Molecular
  • Molecular Structure
  • Prolyl-Hydroxylase Inhibitors / chemistry
  • Prolyl-Hydroxylase Inhibitors / pharmacology*
  • Pyrimidinones / chemistry
  • Pyrimidinones / pharmacology*
  • Structure-Activity Relationship

Substances

  • Prolyl-Hydroxylase Inhibitors
  • Pyrimidinones
  • 4-hydroxypyrimidine
  • EGLN1 protein, human
  • Hypoxia-Inducible Factor-Proline Dioxygenases