Discovery of neuroprotective agents that inhibit human prolyl hydroxylase PHD2.

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\xa0μM and 23\xa0μM 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.