Aza-, Oxa-, and Thia-Pregnan Compounds for GABA A Modulation
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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 and barbiturates have limitations and new neuroactive steroids are required to address various neurological conditions.
Innovation Solution
Development of aza-, oxa-, and thia-pregnan-20-one-3α-ol compounds that act as GABA modulators, targeting the GABA A receptor to treat CNS-related disorders such as depression, schizophrenia, and other conditions by administering these compounds orally, subcutaneously, or intravenously.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If existing agents like benzodiazepines and barbiturates are used to modulate brain excitability, then CNS-related disorders can be treated, but limitations in efficacy and side effects persist
Solution Approach 1:
The patent applies parameter changes by modifying the chemical structure of neuroactive steroids through substitution at specific positions (C1, C2, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19, C20, C21, C22, C23, C24, C25, C26, C27, C28, C29, C30) with various groups including halogen, alkyl, alkoxy, hydroxyl, nitro, cyano, amino, carboxyl, and heterocyclic groups. These structural parameter changes create compounds with improved therapeutic profiles while reducing side effects associated with conventional agents.
Solution Approach 2:
The patent employs composite materials by combining the pregnane steroid core structure with diverse substituent groups to create hybrid molecules that exhibit both the desired CNS therapeutic effects and reduced adverse properties. The composite structure integrates the pharmacophore elements needed for GABA receptor modulation while incorporating modifications that minimize harmful interactions.
2Reliability
If new neuroactive steroid compounds are developed to overcome limitations of existing agents, then therapeutic benefits improve, but compound complexity increases
Solution Approach 1:
The patent applies segmentation by dividing the steroid molecule into distinct functional regions: the core pregnane structure (rings A-D) and various substituent positions that can be independently modified. This segmentation allows systematic optimization of different molecular regions to achieve desired therapeutic effects while managing overall complexity through modular design.
Solution Approach 2:
The patent implements universality by designing a platform compound (pregnane derivative) that can serve multiple therapeutic indications for CNS disorders including anxiety, depression, epilepsy, and schizophrenia. The multi-functional steroid core can be adapted to treat various conditions while maintaining a consistent structural framework, reducing the need for entirely separate drug development programs.
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 brain excitability and treat CNS disorders by enhancing or reducing neuronal activity, providing therapeutic benefits for conditions like depression and schizophrenia.
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, rendering the neuron less susceptible to excitatory inputs
Data Source
AI summary
Provided herein is a compound of Formula (I-I), or a pharmaceutically acceptable salt thereof, wherein the variables are defined herein. Also provided herein are pharmaceutical compositions comprising a compound of Formula (I-I), and methods of using the compounds, e.g., in the treatment of CNS-related disorders.