Alpha-7 Nicotinic Agonists for Cognitive Deficits

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Solution Overview

Problem

Current therapies for schizophrenia and Alzheimer's disease are limited in effectively addressing negative symptoms, cognitive deficits, and side effects, while also failing to significantly improve cognitive function and delay institutionalization in Alzheimer's patients.

Innovation Solution

Development of compounds that act as α7 nicotinic receptor agonists and partial agonists, which can be used to treat various central nervous system disorders by binding to the α7 receptor, improving cognitive function, reducing inflammation, and potentially modifying disease progression in neurodegenerative conditions.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If current antipsychotic agents are used to treat schizophrenia, then positive symptoms are reduced, but negative symptoms and cognitive deficits are not relieved

Engineering Contradiction:

Improveefficacy against positive symptomsVSAvoidefficacy against negative symptoms and cognitive deficits

Core Design Contradiction:

ReliabilityVSAdaptability or versatility

Solution Approach 1:

The patent changes the pharmacological target parameter from dopamine D2 receptors to alpha-7 nicotinic acetylcholine receptors. This parameter change enables the compound to address negative symptoms and cognitive deficits while maintaining efficacy against positive symptoms, thereby resolving the contradiction between treating positive symptoms and addressing negative symptoms/cognitive deficits

Inventive Principle:

Principle #35Parameter changes

2Reliability

If current antipsychotic agents are used to treat schizophrenia, then positive symptoms are reduced, but unwanted side effects occur

Engineering Contradiction:

Improveefficacy against positive symptomsVSAvoidunwanted side effects

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The patent changes the receptor target parameter from dopamine D2 to alpha-7 nAChR, which has a different side effect profile. This parameter change maintains therapeutic efficacy while reducing unwanted side effects such as extrapyramidal symptoms and metabolic disturbances associated with dopamine antagonists

Inventive Principle:

Principle #35Parameter changes

3Reliability

If current Alzheimer's disease therapies are used, then some symptomatic relief is provided, but cognitive function is not significantly improved and institutionalization is not delayed

Engineering Contradiction:

Improvesymptomatic reliefVSAvoidcognitive function improvement and delay of institutionalization

Core Design Contradiction:

ReliabilityVSProductivity

Solution Approach 1:

The patent changes the therapeutic target parameter to alpha-7 nicotinic acetylcholine receptors, which are implicated in cognitive functions including memory and learning. This parameter change provides symptomatic relief while also significantly improving cognitive function and delaying institutionalization in Alzheimer's patients

Inventive Principle:

Principle #35Parameter changes

Data Source

PatentUS9458179B2Quinuclidine, 1-azabicyclo[2.2.1]heptane, 1-azabicyclo [3.2.1]octane, and 1-azabicyclo[3.2.2]nonane compounds as alpha-7 nicotinic acetylcholine receptor ligands

Publication Date: 2016.10.04 BRISTOL MYERS SQUIBB CO

AI summary

The disclosure provides compounds of formula I, including their salts, as well as compositions and methods of using the compounds. The compounds are ligands for the nicotinic α7 receptor and may be useful for the treatment of various disorders of the central nervous system, especially affective and neurodegenerative disorders.