Deuterium-Enriched Cyclohexanone NMDA Modulators
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Solution Overview
Problem
Current NMDA receptor modulators, such as ketamine, have limitations including short-lived effects, side effects, and ambiguous neuroprotective and neurodegenerative effects, with varying bioavailability and metabolism that affect their clinical utility for disorders like pain and neurodegenerative diseases.
Innovation Solution
Development of deuterium-enriched cyclohexanone-based NMDA receptor modulators and their pharmaceutically acceptable salts or prodrugs, which offer improved pharmacokinetics, reduced metabolism, and enhanced clinical effects by modulating NMDA receptors for treating conditions like pain and neurodegenerative disorders.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Speed
If traditional NMDA receptor modulators like ketamine are used, then rapid anesthetic and analgesic effects are achieved, but the duration of action is short-lived
Solution Approach 1:
The patent substitutes hydrogen atoms with deuterium atoms in the cyclohexanone structure, changing the isotopic composition parameter. This isotopic substitution strengthens C-D bonds versus C-H bonds, reducing metabolic degradation rate and extending the duration of action while maintaining the rapid onset characteristics of the parent compound
2Reliability
If NMDA receptor modulators are administered, then therapeutic effects are achieved, but metabolism and bioavailability variability limit clinical utility
Solution Approach 1:
By changing the isotopic parameter (hydrogen to deuterium substitution), the patent reduces the metabolic rate of the compound. The C-D bond strength increases compared to C-H bonds, making the compound more resistant to enzymatic degradation by CYP3A4 and other metabolizing enzymes, thereby reducing inter-individual variability in metabolism and bioavailability
3Reliability
If ketamine and related agents are used for NMDA receptor modulation, then anesthetic and analgesic effects are achieved, but side effects and ambiguous neuroprotective effects occur
Solution Approach 1:
The isotopic substitution of deuterium for hydrogen changes the pharmacokinetic parameters without significantly altering the pharmacodynamic profile. The extended half-life and reduced metabolism lead to more stable plasma concentrations, potentially reducing peak-related side effects while maintaining therapeutic efficacy
Solution Approach 2:
The patent converts the metabolic vulnerability (harmful factor) into a benefit by using deuterium substitution. The same metabolic pathways that normally rapidly degrade ketamine are slowed down, transforming the short half-life limitation into an extended duration of action with potentially reduced side effect profile
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 deuterium-enriched compounds provide prolonged action, reduced side effects, and increased bioavailability, effectively managing NMDA receptor-mediated disorders with improved safety and efficacy compared to traditional modulators.
Implementation Method 1
Ketamine is subject to extensive first-pass metabolism, mainly through oxidation catalyzed by CYP3A4. Deuterium-enriched compounds provide prolonged action and reduced metabolism.
Data Source
AI summary
Disclosed herein are substituted cyclohexanone-based NMDA receptor modulators of Formula I, process of preparation thereof, pharmaceutical compositions thereof, and methods of use thereof.