Branched Alkoxyalkyl Esters for Antiviral Phosphonate Stability
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Solution Overview
Problem
Orally administered alkoxyalkyl esters of phosphonates and phosphates, such as hexadecyloxypropyl cidofovir, face rapid metabolism in the liver and intestine, leading to degradation and reduced antiviral efficacy due to omega and beta oxidation, resulting in short-chain inactive metabolites that are quickly excreted.
Innovation Solution
Development of terminal or penultimate branched chain, unsaturated, and halogen-substituted alkoxyalkyl esters that slow down metabolic inactivation by incorporating blocking groups like alkyl, cyclopropyl, or halogen substituents at the penultimate carbon of the alkyl chain, stabilizing the compounds during absorption and distribution.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Duration of action of moving object
If straight chain alkoxyalkyl esters of phosphonates are used for oral administration, then antiviral activity is achieved, but rapid metabolism occurs leading to short duration of action
Solution Approach 1:
The patent introduces branching at specific positions (penultimate or antepenultimate carbon) of the alkyl chain to create local structural variations. This local modification prevents omega and beta oxidation by blocking the linear degradation pathway, thereby extending the duration of antiviral action without affecting the overall molecular function
Solution Approach 2:
The patent systematically varies the position and type of branching (penultimate vs. antepenultimate, different alkyl groups) to optimize metabolic stability. These parameter changes in molecular structure directly impact the drug's resistance to metabolic degradation, extending its half-life and duration of action
2Quantity of substance
If alkoxyalkyl esters are administered orally, then antiviral efficacy is achieved, but rapid degradation in liver and intestine reduces plasma levels
Solution Approach 1:
The patent preemptively blocks the metabolic degradation pathway by introducing branching groups that prevent omega oxidation and beta oxidation. This preliminary structural modification protects the drug from rapid metabolism in the liver and intestine, maintaining higher plasma concentrations over time
Solution Approach 2:
The patent converts the potential harm of metabolic degradation into a benefit by strategically placing branching groups that slow down oxidation. The metabolic pathways that would normally rapidly degrade the drug are redirected or blocked, transforming a degradation-prone structure into a metabolically stable one
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 modified esters exhibit marked stability against degradation, maintaining higher plasma levels and antiviral efficacy, with compounds like 15-methyl-HDP-CDV showing slower degradation compared to straight chain derivatives, effectively prolonging the pharmacologic effect.
Implementation Method 1
rapid metabolism in the liver and intestine, leading to degradation and reduced antiviral efficacy due to omega and beta oxidation
Data Source
AI summary
The present invention relates to phosphonate, nucleoside phosphonate or nucleoside phosphate compounds, compositions containing them, processes for obtaining them, and their use in treating a variety of medical disorders, in particular viral infections, cancers and the like.