This grant builds upon the research from a prior grant: Optimization of Selective Mu Opioid Receptor Antagonists for the Treatment of Levodopa-Induced Dyskinesias in Parkinson's Disease
Promising Outcomes of Original Grant:
The major objectives of the original grant were to improve upon the μ receptor (MOR) selectivity of ADC5510 and to find compounds that had superior pharmacokinetic profiles compared to ADC5510. We explored the structure-activity relationships of the ADC5510 scaffold and discovered new structural classes of compounds that were tested for MOR selectivity and central antagonism of the analgesic effect of morphine. We were successful in identifying a novel class of MOR antagonists that are more selective and demonstrate significant pharmacokinetic improvements, relative to ADC5510.
Objectives for Supplemental Investigation:
The revised study plan calls for the inclusion of studies to be performed that may provide insight into the CNS penetration of our novel MOR antagonists, and thereby assist in the selection of doses for an efficacy study in a pre-clinical model for reduction of levodopa-induced dyskinesia. ADC5510 has an inverted U-shape dose-response relationship with respect to the reduction in levodopa-induced dyskinesia and the reason for the shape of the dose-response relationship is unclear. By increasing our knowledge of CNS penetration of ADC5510 and new MOR antagonists with improved receptor selectivity, we improve the odds of choosing the right compound and doses to be tested for efficacy. Additionally, by making new MOR antagonists with greater MOR selectivity we can evaluate whether a loss of MOR selectivity is in part responsible for the inverted U-shape dose-response relationship observed with ADC5510.
Importance of This Research for the Development of a New PD Therapy:
Based on the initial efficacy data with ADC5510 for reduction of levodopa-induced dyskinesia, it is anticipated that a compound with greater MOR selectivity and optimized DMPK properties will demonstrate efficacy in the pre-clinical model. Once efficacy in the dyskinesia model has been established, IND-enabling toxicology studies will be performed so that the compound can be tested in initial Phase I proof of concept studies in patients with dyskinesia. The use of selective MOR antagonists for the treatment of levodopa-induced dyskinesia represents a novel treatment paradigm.
The major objectives of the original grant were to improve upon the μ receptor (MOR) selectivity of ADC5510 and to find compounds that had superior pharmacokinetic profiles compared to ADC5510. We explored the structure-activity relationships of the ADC5510 scaffold and discovered new structural classes of compounds that were tested for MOR selectivity and central antagonism of the analgesic effect of morphine. We were successful in identifying a novel class of MOR antagonists that are more selective and demonstrate significant pharmacokinetic improvements, relative to ADC5510.
Objectives for Supplemental Investigation:
The revised study plan calls for the inclusion of studies to be performed that may provide insight into the CNS penetration of our novel MOR antagonists, and thereby assist in the selection of doses for an efficacy study in the pre-clinical model for reduction of levodopa-induced dyskinesia. ADC5510 has an inverted U-shape dose-response relationship with respect to the reduction in levodopa-induced dyskinesia and the reason for the shape of the dose-response relationship is unclear. By increasing our knowledge of CNS penetration of ADC5510 and new MOR antagonists with improved receptor selectivity, we improve the odds of choosing the right compound and doses to be tested for efficacy. Additionally, by making new MOR antagonists with greater MOR selectivity we can evaluate whether a loss of MOR selectivity is in part responsible for the inverted U-shape dose-response relationship observed with ADC5510.
Importance of This Research for the Development of a New PD Therapy:
Based on the initial efficacy data with ADC5510 for reduction of levodopa-induced dyskinesia, it is anticipated that a compound with greater MOR selectivity and optimized DMPK properties will demonstrate efficacy in the pre-clinical model . Once efficacy in the dyskinesia model has been established, IND-enabling toxicology studies will be performed so that the compound can be tested in initial Phase I proof of concept studies in patients with dyskinesia. The use of selective MOR antagonists for the treatment of levodopa-induced dyskinesia represents a novel treatment paradigm.
Progress Report
In Parkinson’s disease, levodopa-induced dyskinesias (LID) are therapeutically limiting side effects that occur with long-term levodopa treatment, and their presence significantly diminishes the quality of life of these patients. Imbalances in opioidergic neurotransmission in brain regions that control movement are thought to contribute to the development and maintenance of LID. Additionally, compounds that act by antagonizing opioid receptors, specifically mu opioid receptors (MOR), may be effective in the treatment of LID. Adolor has shown that a prototypic MOR antagonist is safe and effective in reducing LID in pre-clinical models, supporting the utility of MOR antagonists for the treatment of LID. The overall objective of the project is to improve upon the pharmacokinetic characteristics of ADC02398865, in order to identify compounds with suitable pharmaceutical properties that warrant further development and advancement into the clinic. From the lead optimization campaign, Adolor has succeeded in identifying several potent and selective MOR antagonists that displayed improved pharmacokinetic properties when compared to ADC02398865. A new lead compound was identified as the best candidate for further studies based on its overall best composite pharmacokinetic and pharmacological profile.