title: Potent and Selective Triazole-Based Inhibitors of the Hypoxia-Inducible Factor Prolyl-Hydroxylases with Activity in the Murine Brain.
abstract: 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.
authors.affiliation: Chemistry Research Laboratory, Department of Chemistry, University of Oxford, Oxford, United Kingdom; Centre for Cellular and Molecular Physiology, University of Oxford, Oxford, United Kingdom.
authors.forename: Mun Chiang
authors.initials: MC
authors.lastname: Chan
authors.affiliation: Chemistry Research Laboratory, Department of Chemistry, University of Oxford, Oxford, United Kingdom.
authors.forename: Onur
authors.initials: O
authors.lastname: Atasoylu
authors.affiliation: Centre for Cellular and Molecular Physiology, University of Oxford, Oxford, United Kingdom.
authors.forename: Emma
authors.initials: E
authors.lastname: Hodson
authors.affiliation: Target Discovery Institute, University of Oxford, Oxford, United Kingdom.
authors.forename: Anthony
authors.initials: A
authors.lastname: Tumber
authors.affiliation: Chemistry Research Laboratory, Department of Chemistry, University of Oxford, Oxford, United Kingdom.
authors.forename: Ivanhoe K H
authors.initials: IK
authors.lastname: Leung
authors.affiliation: Chemistry Research Laboratory, Department of Chemistry, University of Oxford, Oxford, United Kingdom.
authors.forename: Rasheduzzaman
authors.initials: R
authors.lastname: Chowdhury
authors.affiliation: Chemistry Research Laboratory, Department of Chemistry, University of Oxford, Oxford, United Kingdom.
authors.forename: Verónica
authors.initials: V
authors.lastname: Gómez-Pérez
authors.affiliation: Chemistry Research Laboratory, Department of Chemistry, University of Oxford, Oxford, United Kingdom.
authors.forename: Marina
authors.initials: M
authors.lastname: Demetriades
authors.affiliation: Chemistry Research Laboratory, Department of Chemistry, University of Oxford, Oxford, United Kingdom.
authors.forename: Anna M
authors.initials: AM
authors.lastname: Rydzik
authors.affiliation: Chemistry Research Laboratory, Department of Chemistry, University of Oxford, Oxford, United Kingdom.
authors.forename: James
authors.initials: J
authors.lastname: Holt-Martyn
authors.affiliation: Centre for Cellular and Molecular Physiology, University of Oxford, Oxford, United Kingdom.
authors.forename: Ya-Min
authors.initials: YM
authors.lastname: Tian
authors.affiliation: Centre for Cellular and Molecular Physiology, University of Oxford, Oxford, United Kingdom.
authors.forename: Tammie
authors.initials: T
authors.lastname: Bishop
authors.affiliation: Chemistry Research Laboratory, Department of Chemistry, University of Oxford, Oxford, United Kingdom.
authors.forename: Timothy D W
authors.initials: TD
authors.lastname: Claridge
authors.affiliation: Chemistry Research Laboratory, Department of Chemistry, University of Oxford, Oxford, United Kingdom.
authors.forename: Akane
authors.initials: A
authors.lastname: Kawamura
authors.affiliation: Centre for Cellular and Molecular Physiology, University of Oxford, Oxford, United Kingdom.
authors.forename: Christopher W
authors.initials: CW
authors.lastname: Pugh
authors.affiliation: Centre for Cellular and Molecular Physiology, University of Oxford, Oxford, United Kingdom.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Ratcliffe
authors.affiliation: Chemistry Research Laboratory, Department of Chemistry, University of Oxford, Oxford, United Kingdom.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Schofield
mesh_terms: D000818:Animals; D001921:Brain / Q000201:enzymology* / Q000473:pathology; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D006367:HeLa Cells; D006801:Humans; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D061986:MCF-7 Cells; D051379:Mice; D020521:Stroke / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D014230:Triazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology
chemical_list: D004791:Enzyme Inhibitors; D014230:Triazoles; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases