19-Nor Steroid Composition for Oral GABA Modulation

Resolve Bottlenecks,
Find Innovative SolutionsGenerate Solutions

Solution Overview

Problem

Existing neuroactive steroids, such as progesterone, are not consistently effective in treating conditions related to brain excitability, including premenstrual syndrome, postnatal depression, and catamenial epilepsy, due to lack of dose-response relationship and potential side effects.

Innovation Solution

Development of 19-nor compounds with C3 disubstitution and a hydrogen at the C10 position, enhancing solubility and pharmacokinetic properties, allowing for oral administration and chronic use as GABA modulators to regulate brain excitability.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If progesterone and its metabolites are used to treat CNS-related conditions, then brain excitability is modulated, but the treatment lacks consistent effectiveness and shows no dose-response relationship

Engineering Contradiction:

Improvetreatment effectivenessVSAvoiddose-response relationship

Core Design Contradiction:

ReliabilityVSAdaptability or versatility

Solution Approach 1:

The patent modifies the chemical structure of progesterone by introducing C3 disubstitution and C10 hydrogenation to create 19-nor compounds. These structural parameter changes produce metabolites with enhanced affinity for GABA receptors, establishing a reliable dose-response relationship where higher doses produce proportionally greater therapeutic effects, thereby resolving the inconsistency in treatment effectiveness.

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The invention creates composite steroid structures by combining the progesterone backbone with specific C3 disubstituted side chains and C10 hydrogenation. This composite molecular design yields metabolites that simultaneously achieve high GABA receptor affinity, predictable pharmacokinetics, and consistent clinical response across different dosing regimens.

Inventive Principle:

Principle #40Composite materials

2Reliability

If progesterone is administered to achieve therapeutic effects, then brain excitability is regulated, but side effects and safety concerns arise

Engineering Contradiction:

Improvetherapeutic benefitVSAvoidside effects

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The patent introduces specific local modifications to the progesterone molecule: C3 disubstitution with electron-withdrawing groups and C10 hydrogenation. These localized structural changes enhance the molecule's ability to produce active metabolites that selectively modulate GABA receptors in the CNS while minimizing off-target effects and metabolic side effects, thereby improving the safety profile.

Inventive Principle:

Principle #3Local quality

Solution Approach 2:

The invention converts the metabolic instability and variable activity of progesterone into a benefit by designing structures that deliberately promote formation of specific active metabolites. The C3 disubstitution and C10 hydrogenation guide metabolic pathways toward producing consistent, high-affinity GABA modulators, transforming unpredictable metabolism into a reliable source of therapeutic activity with reduced side effects.

Inventive Principle:

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

3Reliability

If existing neuroactive steroids are used, then some therapeutic effect is achieved, but solubility and pharmacokinetic properties are insufficient for optimal oral administration

Engineering Contradiction:

Improvetherapeutic effectVSAvoidoral bioavailability

Core Design Contradiction:

ReliabilityVSEase of operation

Solution Approach 1:

The patent modifies physicochemical parameters of the steroid molecule through C3 disubstitution and C10 hydrogenation. These changes alter the molecule's solubility characteristics and metabolic stability, enabling reliable oral absorption and predictable pharmacokinetics while maintaining potent GABA modulatory activity, thus achieving both therapeutic effectiveness and ease of oral administration.

Inventive Principle:

Principle #35Parameter changes

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 19-nor compounds effectively modulate GABA receptors, providing therapeutic benefits for CNS-related conditions like insomnia, depression, and seizure disorders with improved safety and efficacy.

Implementation Method 1

GABA regulates the excitability of individual neurons by regulating the conductance of chloride ions across the neuronal membrane

Methodology Applied

Scientific EffectIon conductance: Conduction (electrical)

Implementation Method 2

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: Electric Field

Implementation Method 3

The 19-nor compounds effectively modulate GABA receptors, providing therapeutic benefits for CNS-related conditions like insomnia, depression, and seizure disorders

Methodology Applied

Scientific EffectGABA receptor modulation:

Data Source

PatentEP4717314A23,3 disubstituted 19-nor pregnane compounds, compositions, and uses thereof

Publication Date: 2026.04.01 SAGE THERAPEUTICS LLC

AI summary

Provided herein are 3,3-disubstituted 19-nor-steroidal compounds according to Formula (I) and (III): where R1, R2, R3, R3', R4, R6a, R6a, R11a, and R11b are as defined herein. Compounds of the present invention are contemplated useful for the prevention and treatment of a variety of CNS-related conditions, for example, treatment of sleep disorders, mood disorders, insomnia, anxiety, depression, traumatic brain injury (TBI), stress, and epilepsy.