Fused Pyridone M1 Allosteric Modulators for Alzheimer's
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Solution Overview
Problem
Current treatments for Alzheimer's Disease, particularly those targeting the muscarinic M1 receptor, face challenges such as side effects like sweating, nausea, and diarrhea, and do not effectively address the underlying disease pathology, while existing therapies like acetylcholinesterase inhibitors provide only symptomatic relief.
Innovation Solution
Development of novel fused pyridone compounds that act as muscarinic M1 receptor positive allosteric modulators, which can be administered to treat Alzheimer's Disease and other disorders involving the M1 receptor, including cognitive impairment, schizophrenia, and sleep disorders, by enhancing the response at the muscarinic receptor without the adverse effects of traditional M1 ligands.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If M1 agonists are used to treat Alzheimer's Disease, then cognitive function is improved and underlying disease mechanism is addressed, but side effects such as sweating, nausea and diarrhea occur
Solution Approach 1:
The patent applies local quality by designing compounds with specific structural features (fused pyridone core with particular substituent patterns) that confer selective affinity for the M1 receptor subtype. This selectivity ensures the therapeutic action is localized to the desired receptor subtype, improving cognitive function while minimizing activation of other muscarinic receptors that would cause unwanted side effects like sweating, nausea and diarrhea.
Solution Approach 2:
The patent employs parameter changes by systematically varying molecular parameters such as substituent types, positions and configurations on the fused pyridone scaffold. By optimizing these chemical parameters, the compounds achieve enhanced M1 receptor selectivity and affinity, thereby improving therapeutic effectiveness while reducing off-target effects that cause adverse reactions.
2Object-affected harmful factors
If acetylcholinesterase inhibitors are used, then symptomatic relief is provided, but underlying disease pathology is not addressed
Solution Approach 1:
The patent applies inversion by shifting from an enzyme inhibition strategy (acetylcholinesterase inhibitors) to a receptor activation strategy (M1 agonists). Instead of preventing acetylcholine breakdown to increase its availability, the invention directly stimulates M1 receptors to produce therapeutic effects, thereby addressing both symptoms and underlying pathology through a fundamentally different mechanistic approach.
Solution Approach 2:
The patent uses M1 receptor agonists as intermediaries to transmit therapeutic effects. These compounds act as mediators that directly engage with and activate M1 receptors, triggering intracellular signaling cascades that address both cholinergic hypofunction and underlying disease mechanisms, including potential effects on amyloid-beta and tau pathology.
Data Source
AI summary
The present invention is directed to fused pyridone compounds of formula (I) (I) that are M1 receptor positive allosteric modulators and that are useful in the treatment of diseases in which the M1 receptor is involved, such as Alzheimer's disease, schizophrenia, pain or sleep disorders. The invention is also directed to pharmaceutical compositions comprising the compounds, and to the use of the compounds and compositions in the treatment of diseases mediated by the M1 receptor.