Naphthalene Carboxamide M1 Allosteric Modulators
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Solution Overview
Problem
Current treatments for Alzheimer's disease, such as acetyl cholinesterase inhibitors, only provide symptomatic relief and are associated with side effects, while M1 receptor agonists have potential to address the underlying disease mechanism but face challenges with side effects like sweating and nausea, and existing M1 ligands do not effectively modulate the muscarinic M1 receptor to treat the disease effectively.
Innovation Solution
Development of naphthalene carboxamide compounds that act as muscarinic M1 receptor positive allosteric modulators, which can be administered alone or in combination with other therapeutically active compounds to treat Alzheimer's disease and other disorders involving the M1 receptor, including cognitive impairment, schizophrenia, pain disorders, and sleep disorders.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If M1 receptor agonists are used to treat Alzheimer's disease, then the underlying disease mechanism can be addressed, but side effects such as sweating and nausea occur
Solution Approach 1:
The patent employs positive allosteric modulators as intermediary substances that indirectly activate M1 receptors rather than directly binding as agonists. These modulators enhance the binding and activity of endogenous acetylcholine at M1 receptors, achieving therapeutic effects while avoiding the harsh side effects associated with direct M1 agonist activation. The allosteric modulation mechanism allows for more selective and graded receptor activation.
Solution Approach 2:
The invention changes the binding parameters and activation characteristics of M1 receptor ligands by using allosteric modulators instead of orthosteric agonists. This parameter change involves binding to a different site on the receptor (allosteric site versus orthosteric site), resulting in modified receptor conformation and activation kinetics that reduce side effects while maintaining therapeutic efficacy.
2Ease of operation
If acetyl cholinesterase inhibitors are used for symptomatic treatment, then cognitive enhancement is achieved, but the underlying disease pathology remains unchanged
Solution Approach 1:
The patent segments the treatment approach into two distinct mechanisms: symptomatic relief through acetylcholinesterase inhibition and disease-modifying effects through M1 receptor allosteric modulation. By combining these segmented approaches, the treatment addresses both immediate cognitive symptoms and underlying pathological processes, creating a comprehensive therapeutic strategy.
Solution Approach 2:
The invention merges two previously separate treatment strategies into a unified approach: using acetyl cholinesterase inhibitors for symptomatic cognitive enhancement while simultaneously employing M1 positive allosteric modulators to address underlying disease pathology. This combination therapy integrates the benefits of both mechanisms to provide comprehensive treatment.
3Reliability
If existing M1 ligands are used to modulate the muscarinic M1 receptor, then receptor activation occurs, but effective disease treatment is not achieved due to side effects
Solution Approach 1:
The patent introduces positive allosteric modulators as intermediary substances that indirectly activate M1 receptors rather than using existing M1 ligands that directly bind. These modulators enhance endogenous acetylcholine activity at M1 receptors, achieving effective disease treatment while minimizing side effects through more selective and physiologically appropriate receptor activation.
Data Source
AI summary
The present invention is directed to naphthalene carboxamide compounds of formula (I) which are M1 receptor positive allosteric modulators and that are useful in the treatment of diseases in which the M1 receptor is involved, such as Alzheimers 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.