Cyclic 10-Substituted Neuroactive Steroids for GABA Modulation
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Solution Overview
Problem
There is a need for new neuroactive steroids that can modulate GABA receptors to address CNS-related disorders, as existing compounds do not fully meet the requirements for efficacy and specificity in treating conditions such as depression and seizures.
Innovation Solution
Development of novel GABA receptor modulating steroids, specifically compounds of Formula (I) and their pharmaceutically acceptable salts, which can be administered orally or intravenously to modulate brain excitability and treat CNS disorders.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If existing neuroactive steroids are used to modulate GABA receptors, then some therapeutic effect is achieved, but efficacy and specificity for treating CNS disorders are insufficient
Solution Approach 1:
The patent introduces specific substituents at defined positions on the steroid core structure (e.g., cyclic groups at position 10, specific configurations at positions 8, 9, 14) to create localized structural variations that enhance both efficacy and specificity for GABA receptor modulation in CNS disorders
Solution Approach 2:
The patent systematically varies multiple structural parameters including stereochemistry (α/β configurations), substituent types (cyclic groups, alkyl groups), and substitution positions to optimize the balance between therapeutic efficacy and disease-specificity, generating a series of analogs with progressively improved properties
2Reliability
If new neuroactive steroid compounds are developed to improve efficacy and specificity, then therapeutic benefits increase, but compound complexity increases
Solution Approach 1:
The patent divides the steroid molecule into distinct functional segments: the core pregnane structure, the 3α-hydroxy-5β configuration, the 20-one group, and various substituents at positions 8, 9, 10, and 14. This modular approach allows systematic optimization of each segment's contribution to efficacy while managing overall molecular complexity
Solution Approach 2:
The patent creates composite steroid structures by combining the established neuroactive 3α-hydroxy-5β-pregnane core with additional cyclic substituents (such as cyclopropyl, cyclobutyl, cyclopentyl groups) at strategic positions, generating compounds with enhanced therapeutic properties while maintaining a manageable structural framework
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 compounds effectively modulate GABA receptors, providing therapeutic benefits for a range of CNS disorders including depression, seizures, and other conditions by altering brain excitability and chloride ion conductance.
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. An intracellular increase in the levels of this anion causes hyperpolarization of the transmembrane potential
Implementation Method 2
The compounds effectively modulate GABA receptors, providing therapeutic benefits for a range of CNS disorders including depression, seizures, and other conditions by altering brain excitability and chloride ion conductance
Data Source
AI summary
Provided herein is a compound of Formula (I) or a pharmaceutically acceptable salt thereof, wherein n, R19, R5, R3a, R6a, R6b, R1, R2a, R2b, R4a, R4b, R7a, R71b, R11a, R11b, R12a, R12b, R17b, R15a, R15b, R16a and R16b 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.