Isotope-Enriched 3APS Derivatives for Metabolic Stability
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Solution Overview
Problem
Existing 3-amino-1-propanesulfonic acid (3APS) compounds face challenges in increasing therapeutic efficacy due to rapid metabolism and limited bioavailability, which affects their effectiveness in treating Alzheimer's disease.
Innovation Solution
Development of isotope-enriched 3-amino-1-propanesulfonic acid derivatives and prodrugs, incorporating deuterium (D) and nitrogen-15 (15N) isotopes, to stabilize the carbon-hydrogen bonds and enhance pharmacokinetic profiles, thereby increasing bioavailability and reducing metabolism.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional 3APS compounds are administered, then they can bind to soluble Aβ peptide and reduce amyloid aggregation, but they are rapidly metabolized and have limited bioavailability, reducing therapeutic efficacy
Solution Approach 1:
The patent applies isotopic substitution (deuterium and nitrogen-15 enrichment) to modify the physical and chemical parameters of the 3APS molecule. This changes the metabolic stability parameter by strengthening C-D bonds compared to C-H bonds, reducing metabolic breakdown while maintaining the molecule's ability to bind to Aβ peptide and reduce amyloid aggregation.
2Duration of action of stationary object
If conventional 3APS compounds are administered, then they can reduce amyloid deposition in the brain, but their rapid metabolism limits their duration of action and requires frequent dosing
Solution Approach 1:
Isotopic enrichment with deuterium and nitrogen-15 modifies the metabolic kinetics parameter of 3APS. The stronger C-D bonds reduce the rate of metabolic cleavage, extending the duration of therapeutic effect and reducing the frequency of dosing required to maintain effective brain levels.
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 isotope-enriched derivatives improve the therapeutic efficacy of 3APS by enhancing bioavailability, stability, and reducing metabolic breakdown, leading to increased brain levels and improved treatment outcomes for Alzheimer's disease.
Implementation Method 1
Carbon-hydrogen bond strength is directly proportional to the absolute value of the ground-state vibrational energy of the bond. This vibrational energy depends on the mass of the atoms that form the bond and increases as the mass of one or both of the atoms making the bond increases. Since deuterium (D) has twice the mass of protium (1H), a carbon-deuterium (C-D) bond is stronger than the corresponding carbon-protium (C-1H) bond.
Implementation Method 2
If a C-1H bond is broken during a rate-determining step of a metabolic reaction, then substituting a deuterium for that protium will cause a decrease in the reaction rate.
Data Source
AI summary
There are provided isotope-enriched compounds of Formula (I) and pharmaceutically acceptable salts or esters thereof, as well as pharmaceutical compositions thereof and methods of use thereof for prevention and treatment of amyloid-β related diseases, such as Alzheimer's disease.R1R2X—CR2—CH2—CH2—SO3H (I)