Deuterated Neuroactive Steroids for GABAA Modulation in CNS Disorders

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Solution Overview

Problem

There is a need for new compounds that can modulate brain excitability and treat CNS-related disorders, as existing agents like benzodiazepines have limitations and new neuroactive steroids are required to improve therapeutic efficacy.

Innovation Solution

Development of deuterium-enriched neuroactive steroids that act as GABA modulators, specifically designed to interact with the GABAA receptor, offering potential therapeutic benefits for CNS-related disorders.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If existing agents like benzodiazepines are used to modulate brain excitability, then therapeutic effects are achieved, but therapeutic efficacy is limited and new compounds are required

Engineering Contradiction:

Improvetherapeutic efficacyVSAvoidneed for new compounds

Core Design Contradiction:

ReliabilityVSAdaptability or versatility

Solution Approach 1:

The patent introduces deuterium substitution at specific positions of neuroactive steroid molecules, changing the isotopic parameter of hydrogen atoms to deuterium. This parameter change enhances the compounds' metabolic stability and potency, thereby improving therapeutic efficacy while providing new chemical entities beyond existing benzodiazepines

Inventive Principle:

Principle #35Parameter changes

2Reliability

If deuterium-enriched neuroactive steroids are developed to improve therapeutic efficacy, then brain excitability modulation is enhanced, but compound complexity increases

Engineering Contradiction:

Improvetherapeutic efficacyVSAvoidcompound complexity

Core Design Contradiction:

ReliabilityVSDevice complexity

Solution Approach 1:

The patent applies deuterium substitution at specific local positions (C2, C6, C16, C17, C21) of the neuroactive steroid molecule rather than throughout the entire molecule. This localized approach enhances therapeutic efficacy at key metabolic sites while minimizing overall molecular complexity and maintaining synthetic feasibility

Inventive Principle:

Principle #3Local quality

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

The deuterium-enriched neuroactive steroids effectively modulate brain excitability, providing treatment options for conditions such as depression, schizophrenia, and other CNS disorders by enhancing GABA receptor interaction.

Implementation Method 1

GABA interacts with its recognition site on the GRC to facilitate the flow of chloride ions down an electrochemical gradient of the GRC into the cell

Methodology Applied

Scientific EffectElectrochemical gradient:

Implementation Method 2

The compounds of the Formula (I) are compounds that comprise deuterium levels that are above the naturally-occurring levels

Methodology Applied

Scientific EffectDeuterium enrichment:

Data Source

PatentUS12534495B2Compositions and methods for treating CNS disorders

Publication Date: 2026.01.27 SAGE THERAPEUTICS LLC

AI summary

Provided herein is a compound of Formula (I)or a pharmaceutically acceptable salt thereof, wherein R3a, R5, R6a, R6b, R17, R21a, R21b, Rm, Rn, R16a, R16b, R7a, R7b, R12a, R12b, R11a, R11b, R2a, R2b, R19, R4a, and R4b are defined herein. Also provided herein are pharmaceutical compositions comprising a compound of Formula (I) and methods of using the compounds, e.g., in the treatment of CNS-related disorders.