19-Substituted Neuroactive Steroids for Consistent GABA Modulation
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Solution Overview
Problem
Existing treatments for conditions related to reduced progesterone levels, such as premenstrual syndrome, postnatal depression, and catamenial epilepsy, are not consistently effective, and there is a need for improved neuroactive steroids that can modulate brain excitability and treat CNS-related disorders.
Innovation Solution
Development of 19-substituted neuroactive steroids that act as GABA modulators, designed to treat CNS-related disorders and induce anesthesia or sedation, including compounds of Formula (I) and their pharmaceutically acceptable salts.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If existing treatments for reduced progesterone levels are used, then some therapeutic effect is achieved, but effectiveness is not consistent
Solution Approach 1:
The patent modifies the chemical structure of neuroactive steroids by introducing specific substituents at the 19-position of the steroid molecule. These structural parameter changes result in compounds with enhanced and more consistent binding affinity to GABA-A receptors, thereby improving therapeutic effectiveness consistency across different conditions such as premenstrual syndrome, postnatal depression, and catamenial epilepsy.
Solution Approach 2:
The invention creates composite neuroactive steroid molecules combining specific steroidæ ¸ with various functional groups at the 19-position. This composite approach allows optimization of both binding affinity and pharmacological activity, resolving the contradiction between reliability of effect and adaptability to different therapeutic scenarios.
2Reliability
If neuroactive steroids are developed to modulate brain excitability, then therapeutic benefits are achieved, but compound complexity increases
Solution Approach 1:
Instead of fundamentally altering the entire steroid molecule, the invention applies local modifications specifically at the 19-position of the steroid nucleus. This localized approach maintains the core pharmacological activity while introducing necessary functional groups to enhance therapeutic benefits, thereby avoiding excessive overall compound complexity.
Solution Approach 2:
The patent systematically varies specific substituents at the 19-position while maintaining the core steroid structure. This segmentation of the molecular structure allows for optimized therapeutic properties without requiring complete redesign of the entire compound, thus managing complexity effectively.
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-substituted neuroactive steroids effectively treat CNS-related disorders and induce anesthesia or sedation, providing therapeutic benefits for conditions like sleep disorders, mood disorders, and seizures, among others, by modulating brain excitability.
Implementation Method 1
GABA regulates the excitability of individual neurons by regulating the conductance of chloride ions across the neuronal membrane. 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.
Data Source
AI summary
Described herein are steroids of Formula (I):and pharmaceutically acceptable salts thereof, wherein R1, R2a, R2b, R3, R4, R5a, R5b, R6, and Z are as defined herein. 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, convulsive 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, and tinnitus.