Envoy Therapeutics’ target discovery technology enables the identification of new drug targets that have very selective expression in brain circuits of therapeutic interest thereby minimizing activity in circuits that may trigger unwanted side effects. The therapeutic benefit of dopamine precursor L-DOPA in treating Parkinson’s disease (PD) is hampered by serious side effects, including L-DOPA -induced dyskinesias (LID), compulsive behaviors and somnolence. Dopamine receptors are broadly distributed throughout the central nervous system (CNS) and consequently this neurotransmitter modulates a wide variety of circuits, including those involved in learning, reward processing, food intake and endocrine regulation. The objective of this project is to develop compounds that precisely correct a motor circuit (”the indirect pathway”) that is compromised in PD via modulation of a novel, highly selectively expressed, non-dopamine receptor target recently identified by Envoy.
Novel small molecule compounds that selectively engage the target of interest have been identified and will be optimized for potency, pharmacokinetic properties and CNS penetration. Lead compounds will then be used to validate the target hypothesis.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
The discovery of novel therapeutics that precisely target the motor circuits disrupted in PD without recourse to intermittent and non-selective stimulation of dopamine receptors offers an exciting opportunity for new treatments with vastly improved side effect profiles. The objective of this project is to ultimately develop an oral therapeutic that provides the Symptoms & Side Effects benefit of dopamine replacement therapy but with sustained efficacy and with minimal acute and long-term side effects.
At the conclusion of the initial phase of the project, it is anticipated that validation of the functional role of the biological target in the indirect pathway will be established. Target validation will then pave the way for the development of compounds suitable for clinical development in order to ultimately provide improved treatment options for PD patients.
Small molecule compounds that selectively act on the target of interest were identified by high throughput screening of compound libraries. The compounds were optimized for potency, selectivity, CNS penetration and pharmacokinetic properties. CNS target occupancy was determined, which then enabled appropriate doses to be selected to successfully confirm robust efficacy in pre-clinical models of Parkinson’s disease. The lead compound in the project is now undergoing safety assessment to enable clinical development.