NMDA Receptor Positive Allosteric Modulators for CNS Disorders

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Solution Overview

Problem

There is a need for new compounds that act as positive allosteric modulators of NMDA receptors to address conditions associated with NMDA receptor function, as existing treatments are inadequate for various CNS-related disorders.

Innovation Solution

The development of specific compounds, represented by Formulas (A-I) to (H-I), which are NMDA receptor positive allosteric modulators, capable of treating CNS-related conditions by enhancing receptor function.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If existing treatments are used for CNS-related disorders, then current standard care is provided, but therapeutic effectiveness is insufficient for NMDA receptor-related conditions

Engineering Contradiction:

Improvetherapeutic effectivenessVSAvoidtreatment coverage for NMDA disorders

Core Design Contradiction:

ReliabilityVSAdaptability or versatility

Solution Approach 1:

The patent develops novel chemical compounds with specific molecular structures (Formulas A-I, B-I, C-I, D-I, E-I, F-I, G-I, H-I) that modulate NMDA receptor activity through controlled chemical parameter variations, achieving therapeutic effects where existing treatments fail

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The invention introduces positive allosteric modulator compounds as intermediary substances that bind to NMDA receptors and enhance their function, serving as a bridge between existing treatments and the desired therapeutic outcome for CNS disorders

Inventive Principle:

Principle #24Intermediary (Mediator)

2Reliability

If NMDA receptors are activated to enhance excitatory neurotransmission, then cognitive and psychiatric conditions are treated, but excitotoxicity may occur

Engineering Contradiction:

Improvecognitive and psychiatric treatment efficacyVSAvoidexcitotoxicity risk

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The patent employs positive allosteric modulators that partially enhance NMDA receptor activity rather than fully activating it, providing sufficient therapeutic benefit for cognitive and psychiatric conditions while avoiding the threshold for excitotoxic damage

Inventive Principle:

Principle #16Partial or excessive action

Solution Approach 2:

The invention converts the potential harmful overactivation of NMDA receptors into a beneficial therapeutic effect by using allosteric modulation to enhance receptor function within a safe range, treating CNS disorders without causing excitotoxicity

Inventive Principle:

Principle #22Blessing in disguise (Convert harm into benefit)

Applied Scientific Principles

This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.

Function Achieved in This Case

These compounds effectively modulate NMDA receptors, providing therapeutic benefits for a range of CNS-related disorders, including anxiety, cognitive disorders, and pain, by enhancing excitatory neurotransmission and reducing excitotoxicity.

Implementation Method 1

NMDA receptors are ligand-gated ion channels that admit Ca2+ after binding of the glutamate and glycine

Methodology Applied

Scientific EffectLigand binding:

Implementation Method 2

NMDA receptors are ligand-gated ion channels that admit Ca2+ after binding of the glutamate and glycine

Methodology Applied

Scientific EffectIon channel conduction: Conduction (electrical)

Data Source

PatentUS20240368214A1Positive NMDA-modulating compounds and methods of use thereof

Publication Date: 2024.11.07 SAGE THERAPEUTICS LLC

AI summary

Compounds are provided according to Formulae (A-I), (B-I), (C-I), (D-I), (E-I), (F-I), (G-I), and (H-I): and pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof. Compounds of the present disclosure are contemplated useful for the prevention and treatment of a variety of CNS-related conditions.