Discovery of neuroprotective agents that inhibit human prolyl hydroxylase PHD2

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...

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Những tác giả chính: Richardson, NL, O'Malley, LJ, Weissberger, D, Tumber, A, Schofield, CJ, Griffith, R, Jones, NM, Hunter, L
Định dạng: Journal article
Ngôn ngữ:English
Được phát hành: Elsevier 2021
Miêu tả
Tóm tắt: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 IC<sub>50</sub> values of 4 μM and 23 μM 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.