Discovery and characterization of selective D4R antagonists and their evaluation in preclinical models of PD-LIDs

PROJECT SUMMARY: Parkinson’s disease (PD) is a chronic and progressive neurodegenerative disorder characterized by the cardinal motor symptoms of resting tremor, hypokinesia, muscle rigidity and bradykinesia. To date, dopamine replacement therapy using the dopamine precursor levodopa, or L-DOPA, remains the gold standard treatment for the motor symptoms in PD. However, development of L-DOPA-induced dyskinesias (LIDs) represents a major dose-limiting adverse effect associated with the long-term treatment of PD using L-DOPA. For example, approximately 10% of PD patients per year develop LIDs within the first 7-8 years of L-DOPA treatment. Moreover, there are no effective treatments for either preventing the development of LIDs or reversing already established LIDs in PD patients. To date, there remains a critical unmet need to develop novel therapeutic approaches for the complications associated with chronic L-DOPA treatment in PD. We have recently discovered a series of dopamine 4 receptor antagonists which are potent and selective for the D4 receptor over the other dopamine isoforms, and a wide selectivity panel. In addition, we have shown that a prototypical compound from this scaffold was capable of producing antidyskinetic action in a mouse model. Subsequently, we have discovered two additional novel scaffolds that show excellent potency and selectivity as D4 antagonists. In this proposal, we will improve and optimize our lead scaffolds in order to improve the ADME properties (metabolic stability) while maintaining the potency and selectivity. In order to develop these best-in-class compounds, we will utilize an iterative medicinal chemistry approach and integrated DMPK studies which will allow us to evaluate potency and selectivity, but also the in vitro and in vivo DMPK properties of newly made compound in a timely manner. The advanced D4 receptor antagonist compounds will then be evaluated in an in vivo animal model of LIDs. These selective D4 receptor antagonist will offer a unique opportunity to help advance the field toward a first-in-class therapeutic agent.