Discovery of neuroprotective agents that inhibit human prolyl hydroxylase PHD2. (15th May 2021)

• Record Type: Journal Article
• Authors: Richardson, Nicole L.; O'Malley, Laura J.; Weissberger, Daniel; Tumber, Anthony; Schofield, Christopher J.; Griffith, Renate; Jones, Nicole M.; Hunter, Luke
• Is Part Of: Bioorganic & medicinal chemistry. Volume 38(2021)
• Publication Date: 2021-05-15
• Subjects: Prolyl hydroxylase -- Hypoxia inducible factor -- Neuroprotection -- Virtual screen -- Oxidative stress -- Docking; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2021.116115
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: 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 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.