Catecholamine Prodrugs for Sustained Parkinson's Symptom Control
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Solution Overview
Problem
Current treatments for Parkinson's disease, such as L-DOPA and apomorphine, face challenges including dyskinesia, off fluctuations, and low oral bioavailability, necessitating the development of efficient, well-tolerated, and orally active dopamine agonists with a stable pharmacokinetic profile.
Innovation Solution
Development of new prodrug derivatives of (4aR,10aR)-1-n-Propyl-1,2,3,4,4a,5,10,10a-octahydro-benzo[g]quinoline-6,7-diol, specifically glucuronide and sulfate conjugates, which are converted in the body to the active compound, providing sustained plasma exposure and avoiding rapid peak concentrations.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If L-DOPA is used as the gold standard treatment, then motor symptoms are effectively controlled, but dyskinesia and off fluctuations occur after several years of treatment
Solution Approach 1:
The patent changes the pharmacokinetic parameters of dopamine agonists by developing prodrugs with modified release profiles. The prodrugs are designed to provide sustained plasma exposure and avoid rapid peak concentrations, thereby maintaining reliable motor symptom control while reducing dyskinesia and off fluctuations associated with conventional L-DOPA treatment.
Solution Approach 2:
The patent applies preliminary action by using prodrugs that are converted in the body to active dopamine agonists. The prodrugs are designed to be converted at a controlled rate, pre-establishing a sustained release profile that prevents harmful fluctuations before they occur.
2Reliability
If apomorphine is used as a dopamine agonist, then motor relief is obtained, but oral bioavailability is low
Solution Approach 1:
The patent uses prodrugs as intermediary compounds that are converted in the body to active dopamine agonists. These prodrugs are designed to overcome the low oral bioavailability issue by being formulated in ways that enhance absorption, while still maintaining the ability to convert to active compounds that provide motor relief.
Solution Approach 2:
The patent changes the pharmacokinetic parameters by developing prodrugs with improved oral bioavailability. The prodrugs are designed to have different absorption, distribution, metabolism, and excretion characteristics that enable oral administration while maintaining therapeutic efficacy.
3Reliability
If conventional dopamine agonists are used, then therapeutic efficacy is achieved, but plasma exposure is rapid and peaks occur
Solution Approach 1:
The patent applies preliminary action by using prodrugs that are converted in the body to active dopamine agonists. The prodrugs are designed to be converted at a controlled rate, pre-establishing a sustained release profile that prevents harmful fluctuations before they occur.
Solution Approach 2:
The patent changes the dynamic plasma exposure profile by using prodrugs with controlled conversion rates. The prodrugs are designed to release the active compound gradually over time, transforming the rapid peak-and-trough profile into a more stable, sustained release profile that maintains therapeutic efficacy without harmful peaks.
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
The prodrug derivatives offer improved oral bioavailability and sustained plasma exposure of the active compound, reducing side effects and maintaining therapeutic efficacy over 24 hours, with potential for higher overall plasma concentrations.
Implementation Method 1
Development of new prodrug derivatives of (4aR,10aR)-1-n-Propyl-1,2,3,4,4a,5,10,10a-octahydro-benzo[g]quinoline-6,7-diol, specifically glucuronide and sulfate conjugates, which are converted in the body to the active compound
Data Source
AI summary
The present invention provides compounds of formula (I) that are prodrugs of catecholamine for use in treatment of neurodegenerative diseases and disorders. The present invention also provides pharmaceutical compositions comprising compounds of the invention and methods of treating neurodegenerative or neuropsychiatric diseases and disorders using the compounds of the invention, in particular Parkinson's disease.Accordingly, the present invention relates to compounds of formula (Id)whereinR1 is H and R2 is selected from one of the substituents (i) and (ii) below; orR1 is selected from one of the substituents (i) and (ii) below and R2 is H; orR1 and R2 are both represented by substituent (i) below; orR1 and R2 are both represented by substituent (ii) below; orR1 is substituent (i) and R2 is substituent (ii); orR1 is substituent (ii) and R2 is substituent (i);wherein * indicates the attachment point; andwherein the carbon atom at the attachment point on substituent (i) is in the S-configuration;or a pharmaceutically acceptable salt thereof.