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© 2015 Chan et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. As part of the cellular adaptation to limiting oxygen availability in animals, the expression of a large set of genes is activated by the upregulation of the hypoxia-inducible transcription factors (HIFs). Therapeutic activation of the natural human hypoxic response can be achieved by the inhibition of the hypoxia sensors for the HIF system, i.e. the HIF prolylhydroxylases (PHDs). Here, we report studies on tricyclic triazole-containing compounds as potent and selective PHD inhibitors which compete with the 2-oxoglutarate co-substrate. One compound (IOX4) induces HIFα in cells and in wildtype mice with marked induction in the brain tissue, revealing that it is useful for studies aimed at validating the upregulation of HIF for treatment of cerebral diseases including stroke.
Author(s): Chan MC, Atasoylu O, Hodson E, Tumber A, Leung IKH, Chowdhury R, Gomez-Perez V, Demetriades M, Rydzik AM, Holt-Martyn J, Tian Y-M, Bishop T, Claridge TDW, Kawamura A, Pugh CW, Ratcliffe PJ, Schofield CJ
Publication type: Article
Publication status: Published
Journal: PLoS ONE
Year: 2015
Volume: 10
Issue: 7
Online publication date: 06/07/2015
Acceptance date: 09/06/2015
ISSN (electronic): 1932-6203
Publisher: Public Library of Science
URL: https://doi.org/10.1371/journal.pone.0132004
DOI: 10.1371/journal.pone.0132004
PubMed id: 26147748
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