Hif prolyl hydroxylase (HPH) has been identified as one of the genes regulated in the brains of Parkinson’s disease patients. Recent research data suggest that HPH is involved in the mechanism regulating the biology important for a dopaminergic phenotype, thus affecting the dopamine synthesis and release capacity of dopaminergic neuronal cells. In addition it is known that inhibiting HPH results in stimulation of a natural defence system in the brain, which is effective against oxidative stress. The working hypothesis for the project is that inhibiting HPH can result in an increased dopamine synthesis capacity of a dopaminergic cell and, in addition, protect the cell against oxidative stress. Thus, compounds inhibiting HPH might be relevant for a Symptoms & Side Effects treatment of Parkinson’s disease, potentially accompanied by a disease modifying effect.
The transcription factor, hypoxia inducible factor (HIF) has been shown to regulate neuroprotective genes and genes important for the cellular dopaminergic phenotype. HIF can be induced by inhibition of the enzyme, HIF prolyl hydroxylase subtype 2 (HPH2). Thus, it was the current goal of the project to identify HPH2 inhibitor compounds, validate those compounds in PD in vitro and in vivo models and subsequently chemically optimize those compounds for further development toward clinical testing. A 62K library was screened in an HPH2 enzymatic assay. A number of active hits were characterized and one 100 nM hit was identified and suggested to bind to the active site. Selected analogues of the 100 nM hit and a few selective HPH inhibitor compounds identified from the literature were tested in PO in vitro models. Several of the compounds were found to increase OA release capacity in PC 12 cells and were neuroprotective in 6-0HDA exposed SH-SY5Y cells which was in line with previous observations (Johansen et al. 20 I0). None of the specific IIPII inhibitor compounds tested and evaluated had suitable brain penetrating properties and a conclusion on their effect in a PO in vivo model could not be reached. Interestingly, a general HIF inducer which inhibits HPH by metal chelation was shown to increase basal OA level and potentiate DA release in the MPTP model for PD.