Selective M4 Antagonist Compounds for Parkinson's Adverse-Effect Control
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Current muscarinic acetylcholine receptor (mAChR) antagonists used for treating Parkinson's disease have dose-limiting adverse effects due to non-selectivity across mAChR subtypes, limiting their clinical efficacy and causing peripheral adverse effects and cognitive disturbances.
Innovation Solution
Development of compounds that selectively target the M4 mAChR subtype to antagonize its function, reducing adverse effects and enhancing therapeutic efficacy for Parkinson's disease and related disorders.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If non-selective mAChR antagonists are used to treat Parkinson's disease, then antiparkinsonian effects are achieved, but dose-limiting adverse effects occur that restrict clinical utility
Solution Approach 1:
The patent applies local quality by designing compounds with selective affinity for specific mAChR subtypes (particularly M1, M3, and M4) rather than non-selective antagonism. The chemical structures are optimized to target specific receptor subtypes expressed in the brain, allowing therapeutic effects to be achieved while minimizing activation of peripheral receptors that cause adverse effects. This subtype-selective approach enables the drug to act locally on central nervous system targets without broadly affecting peripheral muscarinic receptors.
2Reliability
If doses of mAChR antagonists are increased to achieve more complete blockade, then antiparkinsonian effects are enhanced, but adverse effects increase
Solution Approach 1:
The patent applies parameter changes by modifying the chemical structure parameters of mAChR antagonists to achieve subtype selectivity. By changing molecular characteristics such as substituent groups, ring structures, and spatial configuration, the compounds exhibit preferential binding to central mAChR subtypes over peripheral receptors. This allows therapeutic doses to be achieved with complete or near-complete blockade of target receptors while maintaining lower overall doses that avoid peripheral toxicity.
3Object-affected harmful factors
If selective M4 antagonists are developed, then peripheral adverse effects are reduced, but compound complexity increases
Solution Approach 1:
The patent applies segmentation by dividing the mAChR antagonist class into distinct subtype-specific agents. Rather than developing a single non-selective compound, the invention segments the therapeutic approach into selective antagonists for M1, M3, and M4 subtypes. Each segmented compound has a tailored molecular structure optimized for its specific target, achieving peripheral selectivity through this functional segmentation of the drug class.
Solution Approach 2:
The patent applies composite materials by creating complex molecular structures that combine multiple structural elements with specific properties. The selective antagonists incorporate various substituent groups, heterocyclic rings, and stereochemical features that collectively provide subtype selectivity. These composite molecular structures integrate multiple functional components that work together to achieve selective binding to central mAChR subtypes while avoiding peripheral receptor interaction.
Data Source
AI summary
Disclosed are compounds of formula (I) wherein G1 is as antagonists of the muscarinic acetylcholine receptor M4 (mAChR M4) for use in the treatment of e.g. a neurodegenerative disorder, a movement disorder, or a brain disorder, such as e.g. Parkinson's disease, drug-induced Parkinsonism, dystonia, Tourette's syndrome, dyskinesias, schizophrenia, cognitive deficits associated with schizophrenia, excessive daytime sleepiness, attention deficit hyperactivity disorder (ADHD), Huntington's disease, chorea, cerebral palsy, and progressive supranuclear palsy. An exemplary compound is e.g. (2,5-difluoro-4-(6-(((3aR,5s,6aS)-2-((tetrahydro-2H-pyran-4-yl)methyl)octahydrocyclopenta[c]pyrrol-5-yl)amino)pyridazin-3-yl)phenyl)(imino)(methyl)-λ6-sulfanone (e.g. example 12; compound no. 7) Pharmacological data on the activity of the compounds in an mAChR M4 cell-based assay are provided (e.g. table 2).TABLE 2Human M4Cpd. No.IC50 (nM)Emin (%)*113.44239.62318.5345846575.4361883746.0385607918.43101.821186.231243.42138.63*% ACh maximum at 30 μM.