Oxysterol Compounds Modulating NMDA Receptor Function

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Solution Overview

Problem

There is a need for new oxysterols that modulate NMDA receptor function for the prevention and treatment of disorders associated with NMDA expression and function, as existing modulators are inadequate in addressing a broad range of NMDA-mediated disorders.

Innovation Solution

The development of new oxysterol compounds, represented by Formula (I) and their pharmaceutically acceptable salts, which can be used in pharmaceutical compositions to treat or prevent various disorders by modulating NMDA receptor function, including CNS-related conditions and gastrointestinal disorders.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Adaptability or versatility

If existing NMDA receptor modulators are used, then some therapeutic effects are achieved, but they are inadequate for addressing a broad range of NMDA-mediated disorders

Engineering Contradiction:

Improverange of treatable disordersVSAvoidtherapeutic efficacy

Core Design Contradiction:

Adaptability or versatilityVSReliability

Solution Approach 1:

The patent modifies the chemical structure of oxysterol compounds by changing parameters such as substituent groups (R1-R11b), ring structures, and stereochemistry to create a series of derivatives with optimized NMDA receptor modulatory activity. This structural parameter optimization enables the compounds to effectively address multiple NMDA-mediated disorders while maintaining therapeutic efficacy

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The optimized oxysterol compounds are designed to serve multiple therapeutic functions across different NMDA-mediated disorders including CNS conditions (Alzheimer's, Parkinson's, depression, schizophrenia) and gastrointestinal disorders (IBS, IBD, constipation). The compounds act as either positive or negative allosteric modulators depending on the specific disorder being treated, demonstrating universal applicability

Inventive Principle:

Principle #6Universality (Multi-functionality)

2Reliability

If new oxysterol compounds with optimized structure are developed, then therapeutic efficacy is improved, but compound complexity increases

Engineering Contradiction:

Improvetherapeutic efficacyVSAvoidmolecular structure complexity

Core Design Contradiction:

ReliabilityVSDevice complexity

Solution Approach 1:

The patent introduces specific local modifications to the oxysterol core structure at particular positions (R1 at C3, R11a/R11b at C27) while keeping the rest of the molecular framework relatively simple and consistent with natural oxysterols. This localized optimization approach enhances therapeutic efficacy without proportionally increasing overall molecular complexity

Inventive Principle:

Principle #3Local quality

Solution Approach 2:

The oxysterol compounds combine the natural oxysterol core structure with various synthetic substituent groups (alkyl, haloalkyl, alkoxy, carbocyclyl, heterocyclyl groups) to create composite molecular structures that leverage both the biological recognition capabilities of the natural core and the tunable properties of synthetic modifications

Inventive Principle:

Principle #40Composite materials

Data Source

PatentUS11279730B2Oxysterols and methods of use thereof

Publication Date: 2022.03.22 SAGE THERAPEUTICS INC

AI summary

Compounds are provided according to Formula (I): and pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof; wherein R1, R2, R3 and R6, R11a, and R11b are as defined herein. Compounds of the present invention are contemplated useful for the prevention and treatment of a variety of conditions.