Discovery of DS44470011: An oral hypoxia-inducible factor prolyl hydroxylase inhibitor for the treatment of renal anemia

Bioorg Med Chem Lett. 2024 Aug 1:108:129799. doi: 10.1016/j.bmcl.2024.129799. Epub 2024 May 15.

Abstract

Inhibition of the hypoxia-inducible factor prolyl hydroxylase (HIF-PHD) represents a promising strategy for discovering next-generation treatments for renal anemia. We identified a pyrimidine core with HIF-PHD inhibitory activity based on scaffold hopping of FG-2216 using crystal structures of HIF-PHD2 in complex with compound. By optimizing the substituents at the 2- and 6- positions of the pyrimidine core, we discovered DS44470011, which improves the effectiveness of erythropoietin (EPO) release in cells. Oral administration of DS44470011 to cynomolgus monkeys increased plasma EPO levels.

Keywords: Erythropoietin (EPO); Hypoxia-inducible factor (HIF); Hypoxia-inducible factor prolyl hydroxylase (HIF-PHD); Renal anemia.

MeSH terms

  • Administration, Oral
  • Anemia* / drug therapy
  • Animals
  • Drug Discovery
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology
  • Erythropoietin
  • Humans
  • Hypoxia-Inducible Factor-Proline Dioxygenases* / antagonists & inhibitors
  • Hypoxia-Inducible Factor-Proline Dioxygenases* / metabolism
  • Macaca fascicularis*
  • Molecular Structure
  • Prolyl-Hydroxylase Inhibitors* / chemical synthesis
  • Prolyl-Hydroxylase Inhibitors* / chemistry
  • Prolyl-Hydroxylase Inhibitors* / pharmacology
  • Pyrimidines / chemical synthesis
  • Pyrimidines / chemistry
  • Pyrimidines / pharmacology
  • Structure-Activity Relationship

Substances

  • Hypoxia-Inducible Factor-Proline Dioxygenases
  • Prolyl-Hydroxylase Inhibitors
  • Pyrimidines
  • Erythropoietin
  • Enzyme Inhibitors