NMDA Receptor Modulator Prodrugs for Depression Treatment
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Solution Overview
Problem
Current antidepressants for major depressive disorder (MDD) and treatment-resistant depression (TRD) have limitations such as delayed onset of efficacy, low remission rates, and severe side effects, and existing NMDA receptor modulators like ketamine and D-cycloserine suffer from psychometric side effects and administration challenges.
Innovation Solution
Development of prodrugs that are modulators of the NMDA receptor, specifically compounds of formula I or their pharmaceutically acceptable salts, which improve permeability and brain exposure, administered as pharmaceutical compositions for treating depression.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Loss of time
If conventional antidepressants are used for MDD and TRD, then they can treat depression, but they have delayed onset of efficacy and low remission rates
Solution Approach 1:
The patent modifies the chemical structure of known NMDA receptor modulators by creating ester prodrugs with different alkyl groups (methyl, ethyl, propyl, isopropyl, cyclopropyl, butyl, isobutyl). These structural parameter changes improve blood-brain barrier penetration and enhance antidepressant efficacy while maintaining the core pharmacological action on NMDA receptors, thereby addressing both delayed onset and low remission rates
2Loss of time
If ketamine is used for MDD treatment, then it has fast onset and antidepressant effect, but it has psychometric side effects and requires intravenous administration
Solution Approach 1:
The patent creates ester prodrugs of NMDA receptor modulators with various alkyl chain lengths and structures. These modifications allow oral administration while maintaining rapid antidepressant onset similar to ketamine. The prodrug design enables better pharmacokinetic properties and reduced psychometric side effects through controlled metabolism to the active parent compound
Solution Approach 2:
The ester prodrug acts as an intermediary form that facilitates oral bioavailability and controlled delivery of the active NMDA receptor modulator. The prodrug is metabolized in the body to release the active parent compound, enabling rapid CNS penetration and antidepressant effect without requiring intravenous administration, while the controlled release profile reduces acute psychometric side effects
3Reliability
If D-cycloserine is used as NMDA receptor modulator, then it has neuroactive properties for depression treatment, but it causes frequent psychopathological stimulation side effects
Solution Approach 1:
The patent modifies the chemical structure of D-cycloserine by creating ester prodrugs with different alkyl groups. These structural changes improve the therapeutic profile by reducing frequent psychopathological stimulation side effects such as anxiety, euphoria, agitation, and gastrointestinal disturbances while preserving the neuroactive properties and antidepressant efficacy through maintained NMDA receptor modulation
Data Source
AI summary
The present invention is directed to novel prodrugs of modulators of the NMDA receptor. Separate aspects of the inventions are directed to pharmaceutical compositions comprising said compounds and uses of the compounds to treat neurological disorders or neuropsychiatric disorders such as depression.