Potent and Selective Triazole-Based Inhibitors of the Hypoxia-Inducible Factor Prolyl-Hydroxylases with Activity in the Murine Brain

• DOI: 10.1371/journal.pone.0132004
• Publication Date: 2015-07-06T14:31:38Z
• Authors: Mun Chiang Chan; Onur Atasoylu; Emma Hodson; Anthony Tumber; Ivanhoe K. H. Leung; Rasheduzzaman Cho...; Verónica Gómez-Pérez; Marina Demetriades; Anna M. Rydzik; James Holt-Martyn; Ya-Min Tian; Tammie Bishop; Timothy D. W. Cla...; Akane Kawamura; Christopher W. Pugh; Peter J. Ratcliffe; Christopher J. Sc...
• Keywords: Hypoxia; Triazole; Hypoxia-Inducible Factors; Hypoxia-Inducible Factor 1; Hydroxylation

As part of the cellular adaptation to limiting oxygen availability in animals, expression a large set genes is activated by upregulation hypoxia-inducible transcription factors (HIFs). Therapeutic activation natural human hypoxic response can be achieved inhibition hypoxia sensors for HIF system, i.e. prolyl-hydroxylases (PHDs). Here, we report studies on tricyclic triazole-containing compounds as potent and selective PHD inhibitors which compete with 2-oxoglutarate co-substrate. One compound (IOX4) induces HIFα cells wildtype mice marked induction brain tissue, revealing that it useful aimed at validating treatment cerebral diseases including stroke.