TDO Inhibitors: A New Treatment Option for Parkinsonís Disease
Therapeutic Pipeline Program, 2014
Study Rationale: † † † † † † † † ††
Tryptophan-2,3-dioxygenase (TDO) is a key enzyme in the tryptophan degradation pathway. In a Parkinsonís disease (PD) model, TDO was identified as a potential therapeutic target. Scientists at the Netherlands Translational Research Center (NTRC) have developed an innovative TDO screening assay (laboratory experiment) and have applied this assay to identify inhibitor compounds. NTRC will improve the potency and properties of these compounds.
Potent inhibitors of TDO can be used as tools to validate TDO inhibition as a viable treatment option for PD.
NTRC has screened nearly 400,000 compounds for their TDO inhibitory activity and has identified several compounds that are attractive starting points for optimization. Researchers will synthesize a variety of closely related compounds in order to identify a clear relationship between the structure of the compound and its TDO inhibitory activity. Establishing this relationship is a vital step to further improve the potency of the compound series and to optimize the compounds to enable them to be efficiently absorbed and distributed.
Impact on Diagnosis/Treatment of Parkinsonís Disease: † † † † † ††
Studies in pre-clinical models have indicated that TDO inhibition might alter the course of PD progression. When sufficiently translated to humans with PD, TDO inhibition could provide a novel disease-modifying therapy.
Next Steps for Development:
Once a compound fulfills our criteria it will be tested in a pharmacokinetic study. High and stable compound levels are important for a compound to be effective in pre-clinical models and, ultimately, in PD patients. † ††
Previously, protein tryptophan-2,3-dioxygenase (TDO) was identified as a potential target for the treatment of Parkinson's disease (PD) in a pre-clinical model. We then developed innovative assays (experimental setups) for the evaluation of human TDO and used these assay to develop compounds that act exactly as TDO does in the human body. Since the beginning of this study, we have developed new compounds that act as TDO but don't have unwanted side effects. These compounds are well suited for the evaluation in advanced pre-clinical models with Parkinson's features.
Presentations & Publications
Presented at: Drug Discovery Summit; June 13 - 14, 2016; Berlin, Germany.
Presented at: World Preclinical Conference; June 14 - 17, 2016; Boston, MA, USA.
Managing Director and Head of Chemistry at Netherlands Translational Research Center B.V.
Location: Oss, Netherlands