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: | Journal article |
| Language: | English |
| Published: |
Public Library of Science
2015
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| _version_ | 1797111884241960960 |
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| author | Chan, MC Atasoylu, O Hodson, E Tumber, A Leung, IKH Chowdhury, R Gómez-Pérez, V Demetriades, M Rydzik, AM Holt-Martyn, J Tian, Y-M Bishop, T Claridge, TDW Kawamura, A Pugh, CW Ratcliffe, PJ Schofield, CJ |
| author_facet | Chan, MC Atasoylu, O Hodson, E Tumber, A Leung, IKH Chowdhury, R Gómez-Pérez, V Demetriades, M Rydzik, AM Holt-Martyn, J Tian, Y-M Bishop, T Claridge, TDW Kawamura, A Pugh, CW Ratcliffe, PJ Schofield, CJ |
| author_sort | Chan, MC |
| collection | OXFORD |
| 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 | 2024-03-07T08:16:42Z |
| format | Journal article |
| id | oxford-uuid:2139f408-d035-4e8d-8f27-2a2cf58fb3f1 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T08:16:42Z |
| publishDate | 2015 |
| publisher | Public Library of Science |
| record_format | dspace |
| spelling | oxford-uuid:2139f408-d035-4e8d-8f27-2a2cf58fb3f12024-01-09T14:26:34ZPotent and selective triazole-based inhibitors of the hypoxia-inducible factor prolyl-hydroxylases with activity in the murine brainJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:2139f408-d035-4e8d-8f27-2a2cf58fb3f1EnglishSymplectic Elements at OxfordPublic Library of Science2015Chan, MCAtasoylu, OHodson, ETumber, ALeung, IKHChowdhury, RGómez-Pérez, VDemetriades, MRydzik, AMHolt-Martyn, JTian, Y-MBishop, TClaridge, TDWKawamura, APugh, CWRatcliffe, PJSchofield, CJAs 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. |
| spellingShingle | Chan, MC Atasoylu, O Hodson, E Tumber, A Leung, IKH Chowdhury, R Gómez-Pérez, V Demetriades, M Rydzik, AM Holt-Martyn, J Tian, Y-M Bishop, T Claridge, TDW Kawamura, A Pugh, CW Ratcliffe, PJ Schofield, CJ Potent and selective triazole-based inhibitors of the hypoxia-inducible factor prolyl-hydroxylases with activity in the murine brain |
| 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 |
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