Potent and Selective Triazole-Based Inhibitors of the Hypoxia-Inducible Factor Prolyl-Hydroxylases with Activity in the Murine Brain.
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...
| Main Authors: | , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2015-01-01
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| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC4492579?pdf=render |
| _version_ | 1818533448138096640 |
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| author | Mun Chiang Chan Onur Atasoylu Emma Hodson Anthony Tumber Ivanhoe K H Leung Rasheduzzaman Chowdhury Verónica Gómez-Pérez Marina Demetriades Anna M Rydzik James Holt-Martyn Ya-Min Tian Tammie Bishop Timothy D W Claridge Akane Kawamura Christopher W Pugh Peter J Ratcliffe Christopher J Schofield |
| author_facet | Mun Chiang Chan Onur Atasoylu Emma Hodson Anthony Tumber Ivanhoe K H Leung Rasheduzzaman Chowdhury Verónica Gómez-Pérez Marina Demetriades Anna M Rydzik James Holt-Martyn Ya-Min Tian Tammie Bishop Timothy D W Claridge Akane Kawamura Christopher W Pugh Peter J Ratcliffe Christopher J Schofield |
| author_sort | Mun Chiang Chan |
| collection | DOAJ |
| description | 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 prolyl-hydroxylases (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. |
| first_indexed | 2024-12-11T17:58:49Z |
| format | Article |
| id | doaj.art-270e114bd2074970b400b2da1562426e |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-12-11T17:58:49Z |
| publishDate | 2015-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-270e114bd2074970b400b2da1562426e2022-12-22T00:55:58ZengPublic Library of Science (PLoS)PLoS ONE1932-62032015-01-01107e013200410.1371/journal.pone.0132004Potent and Selective Triazole-Based Inhibitors of the Hypoxia-Inducible Factor Prolyl-Hydroxylases with Activity in the Murine Brain.Mun Chiang ChanOnur AtasoyluEmma HodsonAnthony TumberIvanhoe K H LeungRasheduzzaman ChowdhuryVerónica Gómez-PérezMarina DemetriadesAnna M RydzikJames Holt-MartynYa-Min TianTammie BishopTimothy D W ClaridgeAkane KawamuraChristopher W PughPeter J RatcliffeChristopher J SchofieldAs 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 prolyl-hydroxylases (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.http://europepmc.org/articles/PMC4492579?pdf=render |
| spellingShingle | Mun Chiang Chan Onur Atasoylu Emma Hodson Anthony Tumber Ivanhoe K H Leung Rasheduzzaman Chowdhury Verónica Gómez-Pérez Marina Demetriades Anna M Rydzik James Holt-Martyn Ya-Min Tian Tammie Bishop Timothy D W Claridge Akane Kawamura Christopher W Pugh Peter J Ratcliffe Christopher J Schofield Potent and Selective Triazole-Based Inhibitors of the Hypoxia-Inducible Factor Prolyl-Hydroxylases with Activity in the Murine Brain. PLoS ONE |
| title | Potent and Selective Triazole-Based Inhibitors of the Hypoxia-Inducible Factor Prolyl-Hydroxylases with Activity in the Murine Brain. |
| title_full | Potent and Selective Triazole-Based Inhibitors of the Hypoxia-Inducible Factor Prolyl-Hydroxylases with Activity in the Murine Brain. |
| title_fullStr | Potent and Selective Triazole-Based Inhibitors of the Hypoxia-Inducible Factor Prolyl-Hydroxylases with Activity in the Murine Brain. |
| title_full_unstemmed | Potent and Selective Triazole-Based Inhibitors of the Hypoxia-Inducible Factor Prolyl-Hydroxylases with Activity in the Murine Brain. |
| title_short | Potent and Selective Triazole-Based Inhibitors of the Hypoxia-Inducible Factor Prolyl-Hydroxylases with Activity in the Murine Brain. |
| title_sort | potent and selective triazole based inhibitors of the hypoxia inducible factor prolyl hydroxylases with activity in the murine brain |
| url | http://europepmc.org/articles/PMC4492579?pdf=render |
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