Design and Synthesis of a Series of Novel Pyrazolopyridines as HIF-1alpha Prolyl Hydroxylase Inhibitors

Bioorg Med Chem Lett. 2006 Nov 1;16(21):5687-90. doi: 10.1016/j.bmcl.2006.08.017.

Abstract

Recently resolved X-ray crystal structure of HIF-1alpha prolyl hydroxylase was used to design and develop a novel series of pyrazolopyridines as potent HIF-1alpha prolyl hydroxylase inhibitors. The activity of these compounds was determined in a human EGLN-1 assay. Structure-based design aided in optimizing the potency of the initial lead (2, IC(50) of 11 microM) to a potent (11l, 190 nM) EGLN-1 inhibitor. Several of these analogs were potent VEGF inducers in a cell-based assay. These pyrazolopyridines were also effective in stabilizing HIF-1alpha.

MeSH terms

  • Cell Line
  • Drug Design*
  • Humans
  • Hypoxia-Inducible Factor-Proline Dioxygenases
  • Procollagen-Proline Dioxygenase / antagonists & inhibitors*
  • Pyrazoles / chemical synthesis*
  • Pyrazoles / pharmacology*
  • Pyridines / chemical synthesis*
  • Pyridines / pharmacology*

Substances

  • Pyrazoles
  • Pyridines
  • pyrazolopyridine
  • EGLN1 protein, human
  • Procollagen-Proline Dioxygenase
  • Hypoxia-Inducible Factor-Proline Dioxygenases