[(4-Hydroxyl-benzo[4,5]thieno[3,2-c]pyridine-3-carbonyl)-amino]-acetic Acid Derivatives; HIF Prolyl 4-hydroxylase Inhibitors as Oral Erythropoietin Secretagogues

Bioorg Med Chem Lett. 2013 Nov 1;23(21):5953-7. doi: 10.1016/j.bmcl.2013.08.067. Epub 2013 Aug 23.

Abstract

A new series of PHD (HIF prolyl 4-hydroxylase) inhibitors was designed based on the X-ray co-crystal structure of FG-2216. Using a lead generation process, a series of [(4-Hydroxyl-benzo[4,5]thieno[3,2-c]pyridine-3-carbonyl)-amino]-acetic acid derivatives was developed as potent PHD2 inhibitors. This class of compounds also showed the ability to stabilize HIF-α, to stimulate EPO secretion in in vitro studies, and to increase hematocrit, red blood cell count, and hemoglobin levels in an animal efficacy study.

Keywords: Erythropoiesis; HIF-PH (PHD); Inhibitor; Stabilizer.

MeSH terms

  • Acetic Acid / chemistry*
  • Acetic Acid / pharmacokinetics
  • Acetic Acid / pharmacology*
  • Animals
  • Cell Line
  • Enzyme Inhibitors / chemistry*
  • Enzyme Inhibitors / pharmacokinetics
  • Enzyme Inhibitors / pharmacology*
  • Erythropoiesis / drug effects
  • Erythropoietin / metabolism*
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism
  • Hypoxia-Inducible Factor-Proline Dioxygenases / antagonists & inhibitors*
  • Hypoxia-Inducible Factor-Proline Dioxygenases / chemistry
  • Hypoxia-Inducible Factor-Proline Dioxygenases / metabolism
  • Male
  • Models, Molecular
  • Pyridines / chemistry
  • Pyridines / pharmacokinetics
  • Pyridines / pharmacology

Substances

  • Enzyme Inhibitors
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Pyridines
  • Erythropoietin
  • Hypoxia-Inducible Factor-Proline Dioxygenases
  • Acetic Acid