N-linked Lactam 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 fail to address the underlying disease pathology effectively.

Innovation Solution

Development of novel N-linked lactam 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.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If M1 agonists are used to treat Alzheimer's Disease, then the underlying disease mechanism may be addressed, but side effects such as sweating, nausea, and diarrhea occur

Engineering Contradiction:

Improveeffectiveness in addressing underlying disease mechanismVSAvoidside effects (sweating, nausea, diarrhea)

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The patent employs positive allosteric modulators as intermediary compounds 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 agonists. The allosteric modulation mechanism allows for more selective and温和 activation of the target receptor.

Inventive Principle:

Principle #24Intermediary (Mediator)

2Ease of operation

If acetyl cholinesterase inhibitors are used, then cognitive enhancement is provided, but the underlying disease pathology is not addressed

Engineering Contradiction:

Improvecognitive enhancementVSAvoidability to address underlying disease pathology

Core Design Contradiction:

Ease of operationVSReliability

Solution Approach 1:

Instead of inhibiting the enzyme that breaks down acetylcholine (acetyl cholinesterase inhibitors), the patent inverts the approach by directly targeting the receptor (M1) with positive allosteric modulators. This reversal strategy moves from indirect enzyme inhibition to direct receptor modulation, potentially providing both symptomatic relief and disease-modifying effects by addressing the underlying cholinergic hypofunction at its source.

Inventive Principle:

Principle #13The other way round (Inversion)

3Reliability

If M1 ligands are developed for Alzheimer's Disease, then potential treatment of underlying mechanism is achieved, but common muscarinic receptor side effects occur

Engineering Contradiction:

Improvepotential to treat underlying disease mechanismVSAvoidside effects common to other muscarinic receptor ligands

Core Design Contradiction:

ReliabilityVSObject-generated harmful factors

Solution Approach 1:

The patent achieves selective modulation of M1 receptors through carefully designed molecular structures with specific substituent patterns. By optimizing the local chemical environment and spatial arrangement of functional groups in the compound structure, the invention enables selective binding to M1 receptors while minimizing interactions with other muscarinic receptor subtypes (M2-M5), thereby reducing off-target side effects.

Inventive Principle:

Principle #3Local quality

Data Source

PatentEP2709451B1N-linked lactam m1 receptor positive allosteric modulators

Publication Date: 2015.12.30 MERCK SHARP & DOHME CORP

AI summary

The present invention is directed to N-linked lactam compounds of general 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 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.