C21-Substituted Neuroactive Steroids for Reliable GABA Modulation
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Solution Overview
Problem
Existing treatments for conditions related to reduced progesterone levels, such as premenstrual syndrome (PMS), postnatal depression (PND), 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 C21-substituted neuroactive steroids that act as GABA modulators, designed to treat conditions like PMS, PND, and catamenial epilepsy, and other CNS-related disorders by administering compounds of Formula (I) or their pharmaceutically acceptable salts, which can be administered orally, subcutaneously, intravenously, or intramuscularly, and potentially through continuous infusion.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If existing treatments for reduced progesterone levels are used, then some therapeutic effect is achieved, but consistency and reliability of treatment are insufficient
Solution Approach 1:
The patent modifies the chemical structure of neuroactive steroids by introducing C21 substituents and varying functional groups at different positions, creating a series of compounds with optimized parameters for binding affinity and selectivity to GABA receptors, thereby improving treatment reliability and consistency
Solution Approach 2:
The invention develops composite steroid molecules combining specific structural elements (C21 substituents, heteroaryl groups, hydroxyl positions) that work synergistically to enhance both reliability of GABA modulation and adaptability across different CNS disorders including PMS, PND, and epilepsy
2Reliability
If C21-substituted neuroactive steroids are developed to modulate brain excitability, then therapeutic efficacy for CNS disorders is improved, but complexity of compound structure increases
Solution Approach 1:
The complex steroid molecule is segmented into distinct functional regions: the core steroid structure, C21 substituent group, and heteroaryl moiety at position 3, allowing systematic optimization of each segment's contribution to therapeutic efficacy while managing overall molecular complexity
Solution Approach 2:
Specific local modifications are introduced at critical positions (C21 substituent, position 3 heteroaryl group, hydroxyl at C11 and C17) to enhance GABA receptor binding affinity and selectivity, achieving improved therapeutic efficacy through targeted local changes rather than global structural complexity
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 provide therapeutic benefits for conditions like PMS, PND, and catamenial epilepsy, as well as other CNS-related disorders, demonstrating efficacy in treating symptoms associated with reduced progesterone levels.
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.
Implementation Method 2
An intracellular increase in the levels of this anion causes hyperpolarization of the transmembrane potential, rendering the neuron less susceptible to excitatory inputs, i.e., reduced neuron excitability.
Data Source
AI summary
Described herein are neuroactive steroids of the Formula (I): or a pharmaceutically acceptable salt thereof; wherein ------, R1, R2, R5, A and L are as defined herein. Such compounds are envisioned, in certain embodiments, to behave as GABA modulators. The present invention also provides pharmaceutical compositions comprising a compound of the present invention and methods of use and treatment, e.g., such for inducing sedation and/or anesthesia.