Aryl Methyl Benzoquinazolinone Modulators for Alzheimer's Disease

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 aryl methyl benzoquinazolinone compounds that act as muscarinic M1 receptor positive allosteric modulators, which can be used to treat Alzheimer's Disease and other disorders by enhancing the function of the M1 receptor, potentially altering APP processing and preventing Aβ peptide formation.

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 treating underlying disease mechanismVSAvoidside effects (sweating, nausea, diarrhea)

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The patent applies local quality by designing compounds with specific structural features (aryl methyl benzoquinazolinone core with particular substituents) that confer selective affinity for the M1 receptor subtype. This selectivity allows the drug to act locally on the M1 receptor in the brain while minimizing activation of other muscarinic receptor subtypes that mediate peripheral side effects, thus addressing the underlying disease mechanism without causing widespread cholinergic stimulation

Inventive Principle:

Principle #3Local quality

Solution Approach 2:

The patent segments the muscarinic receptor system by developing compounds that specifically target the M1 receptor subtype rather than acting on all muscarinic receptors non-selectively. This segmentation is achieved through careful molecular design that exploits structural differences between M1 and other muscarinic subtypes, allowing selective modulation of central cholinergic function while sparing peripheral receptors responsible for gastrointestinal and sudorific side effects

Inventive Principle:

Principle #1Segmentation

2Ease of operation

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

Engineering Contradiction:

Improvesymptomatic cognitive enhancementVSAvoidaddressing underlying disease pathology

Core Design Contradiction:

Ease of operationVSReliability

Solution Approach 1:

The patent inverts the conventional approach by instead of inhibiting acetylcholinesterase to increase acetylcholine levels, it directly stimulates the M1 receptor to activate downstream signaling pathways. This inversion shifts the mechanism from symptomatic enhancement through increased neurotransmitter availability to direct receptor activation that can trigger neuroprotective and disease-modifying effects, including inhibition of beta-secretase and reduction of amyloid-beta production

Inventive Principle:

Principle #13The other way round (Inversion)

3Adaptability or versatility

If non-selective muscarinic receptor ligands are used, then broad muscarinic receptor activation occurs, but selective therapeutic benefit for Alzheimer's Disease is reduced

Engineering Contradiction:

Improvebroad muscarinic receptor activationVSAvoidselective therapeutic benefit

Core Design Contradiction:

Adaptability or versatilityVSReliability

Solution Approach 1:

The patent applies local quality by designing compounds with specific structural features (aryl methyl benzoquinazolinone core with particular substituents) that confer selective affinity for the M1 receptor subtype. This selectivity allows the drug to act locally on the M1 receptor in the brain while minimizing activation of other muscarinic receptor subtypes that mediate peripheral side effects

Inventive Principle:

Principle #3Local quality

Solution Approach 2:

The patent segments the muscarinic receptor system by developing compounds that specifically target the M1 receptor subtype rather than acting on all muscarinic receptors non-selectively. This segmentation is achieved through careful molecular design that exploits structural differences between M1 and other muscarinic subtypes

Inventive Principle:

Principle #1Segmentation

Data Source

PatentUS9708273B2Aryl methyl benzoquinazolinone M1 receptor positive allosteric modulators

Publication Date: 2017.07.18 MERCK SHARP & DOHME LLC

AI summary

The present invention is directed to benzoquinazilinone 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 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.