Citrate Salt Forms of Muscarinic Agonists for M1/M4 Selectivity
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Solution Overview
Problem
Existing muscarinic receptor agonists used in treating conditions like Alzheimer's disease and schizophrenia suffer from significant cholinergic side effects, such as nausea, gastrointestinal issues, and bradycardia, due to lack of selectivity for M1 and M4 receptor subtypes over M2 and M3.
Innovation Solution
Development of citrate salts of compounds, particularly citrate monohydrate salts, that exhibit high selectivity for M1 and/or M4 muscarinic receptor subtypes, reducing peripheral side effects and enhancing therapeutic efficacy.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If non-selective muscarinic receptor agonists are used to treat cognitive disorders, then cholinergic replacement therapy efficacy is achieved, but peripheral side effects (nausea, gastrointestinal issues, bradycardia) occur due to stimulation of M2 and M3 receptors
Solution Approach 1:
The patent applies local quality by designing compounds with specific molecular structures that exhibit differential binding affinity to different muscarinic receptor subtypes. The compounds are engineered to preferentially activate central M1 receptors while having reduced affinity for peripheral M2 and M3 receptors, thereby achieving localized therapeutic action in the CNS with minimized peripheral effects
Solution Approach 2:
The patent employs parameter changes by modifying key molecular parameters of the agonist compounds, including the basic nitrogen pKa (optimized between 7-9), lipophilicity (logP values), and steric properties. These parameter optimizations enable the compounds to cross the blood-brain barrier effectively while maintaining selective affinity for central muscarinic receptors over peripheral ones
2Reliability
If acetylcholinesterase inhibitors are used to prevent breakdown of endogenous acetylcholine, then symptomatic cognitive decline is improved, but dose-limiting side effects occur from stimulation of peripheral M2 and M3 receptors
Solution Approach 1:
The patent applies the taking out principle by extracting the problematic non-selective property from the therapeutic approach. Instead of using non-selective acetylcholinesterase inhibitors that increase acetylcholine throughout the body, the invention introduces selective M1/M4 agonists that directly target central receptors, thereby removing the source of peripheral side effects while preserving cognitive benefits
Solution Approach 2:
The patent uses intermediary compounds with specific pharmacological properties as mediators between the therapeutic goal and the biological system. These selective agonists act as intermediaries that achieve cognitive improvement through central receptor activation without triggering peripheral cholinergic responses, thus mediating the therapeutic effect while avoiding harmful side effects
3Reliability
If direct M1 agonists are developed to target cognitive function, then pre-clinical efficacy is achieved, but selectivity over M2 and M3 receptors must be optimized to reduce side effects
Solution Approach 1:
The patent applies segmentation by dividing the molecular structure into distinct functional segments: a basic nitrogen-containing core for receptor binding, aromatic substituents for affinity modulation, and side chains for selectivity control. This segmented approach allows systematic optimization of each component to achieve both cognitive efficacy and M1/M4 selectivity
Solution Approach 2:
The patent employs composite molecular structures combining heterocyclic rings (pyrazole, imidazole), piperidine moieties, and spirocyclic frameworks. These composite structures integrate multiple pharmacophoric elements that work synergistically to provide selective binding to central muscarinic receptors while maintaining appropriate pharmacokinetic properties
Data Source
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AI summary
This invention relates to compounds and salts thereof that are muscarinic receptor agonists and which are useful in the treatment of muscarinic receptor mediated diseases. Also provided are crystalline forms of the compounds and salts thereof; pharmaceutical compositions containing the compounds and salts thereof, or crystalline forms thereof; therapeutic uses of the compounds and salts thereof, or crystalline forms thereof; methods of synthesis thereof; and intermediates useful in said methods of synthesis.