19-Nor Neuroactive Steroids Modulating Brain Excitability

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Solution Overview

Problem

Current treatments for conditions associated with reduced progesterone levels, such as premenstrual syndrome, postnatal depression, and catamenial epilepsy, are inadequate due to inconsistent effectiveness and side effects of existing progesterone therapies.

Innovation Solution

Development of novel 19-nor neuroactive steroids with disubstitution at the C3 position and a hydrogen at the C19 position, enhancing pharmacokinetic properties, solubility, and reducing toxicity, which act as GABA modulators to regulate brain excitability.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If existing progesterone therapies are used to treat conditions associated with reduced progesterone levels, then therapeutic effects are achieved, but inconsistent effectiveness and side effects occur

Engineering Contradiction:

Improvetherapeutic effectivenessVSAvoidside effects

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The patent modifies the chemical structure of neuroactive steroids by introducing disubstitution at the C3 position and removing the methyl group at C19 (19-nor configuration). These structural parameter changes improve pharmacokinetic properties, enhance solubility, and reduce toxicity while maintaining GABA modulator activity, thereby resolving the contradiction between therapeutic effectiveness and side effects

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The invention creates composite molecular structures combining the neuroactive steroid core with specific substituents at C3 position (such as hydroxy groups and other functional groups). This composite approach optimizes both therapeutic efficacy and safety profile by integrating multiple functional moieties into a single molecular entity

Inventive Principle:

Principle #40Composite materials

2Reliability

If progesterone and its metabolites are administered to regulate brain excitability, then brain excitability is modulated, but pharmacokinetic properties and solubility are insufficient

Engineering Contradiction:

Improvebrain excitability modulationVSAvoidpharmacokinetic properties

Core Design Contradiction:

ReliabilityVSEase of manufacture

Solution Approach 1:

The patent systematically modifies molecular parameters including substitution patterns at C3, removal of C19 methyl group, and optimization of stereochemistry. These changes collectively improve pharmacokinetic properties (absorption, distribution, metabolism, excretion) and solubility while preserving the ability to modulate brain excitability through GABA receptor interaction

Inventive Principle:

Principle #35Parameter changes

3Reliability

If neuroactive steroids are used to treat CNS-related disorders, then therapeutic efficacy is achieved, but toxicity increases

Engineering Contradiction:

Improvetherapeutic efficacyVSAvoidtoxicity

Core Design Contradiction:

ReliabilityVSObject-generated harmful factors

Solution Approach 1:

The patent employs structural parameter optimization by introducing disubstitution at C3 position with specific functional groups and eliminating the C19 methyl group. These modifications reduce metabolic toxicity and improve safety margin while maintaining potent GABA modulator activity, effectively resolving the toxicity-efficacy contradiction

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

These compounds provide improved therapeutic efficacy and safety for treating CNS-related disorders by effectively modulating brain excitability, offering a more reliable option for conditions linked to progesterone level fluctuations.

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 EffectGABA receptor modulation:

Implementation Method 2

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

Methodology Applied

Scientific EffectIon conductance regulation:

Data Source

PatentUS11912737B219-nor neuroactive steroids and methods of use thereof

Publication Date: 2024.02.27 SAGE THERAPEUTICS LLC

AI summary

Provided herein are 3,3-disubstituted 19-nor-steroidal compounds according to Formula (I):and pharmaceutical compositions thereof. Such compounds are contemplated useful for the prevention and treatment of a variety of CNS-related conditions, for example, treatment of sleep disorders, mood disorders, schizophrenia spectrum disorders, disorders of memory and/or cognition, movement disorders, personality disorders, autism spectrum disorders, pain, traumatic brain injury, vascular diseases, substance abuse disorders and/or withdrawal syndromes, tinnitus, status epilepticus.