Phosphonate Nucleosides Enhancing Membrane Permeability
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Current antiviral agents face challenges in effectively treating viral disorders due to issues like poor cell membrane permeability and resistance, particularly for HIV, hepatitis B, and C, necessitating the development of new phosphonucleoside derivatives with improved therapeutic efficacy.
Innovation Solution
The development of phosphonucleoside derivatives with specific structural modifications, including various substituents and linkages, to enhance their ability to inhibit viral enzymes like reverse transcriptase, potentially bypassing initial phosphorylation steps and improving membrane permeability.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional nucleoside analogues are used as antiviral agents, then they can inhibit viral replication through competitive inhibition and chain termination, but they suffer from poor cell membrane permeability and require conversion to active triphosphate form which is labile
Solution Approach 1:
The patent changes the chemical structure parameter by replacing the phosphate group with a phosphonate group, which has similar biochemical function but improved stability and permeability characteristics. This structural parameter change allows the compound to maintain antiviral activity while overcoming the limitations of poor membrane permeability and metabolic instability
Solution Approach 2:
The phosphonate group acts as an intermediary between the nucleoside analog and the viral reverse transcriptase enzyme. It mimics the natural phosphate group sufficiently to be recognized by the enzyme and incorporated into the viral DNA, yet it provides improved pharmacokinetic properties including better membrane permeability and metabolic stability
2Reliability
If phosphonate groups are introduced to improve stability and bypass phosphorylation, then fewer phosphorylation steps are required, but the structural complexity increases
Solution Approach 1:
The patent modifies the molecular structure by introducing a phosphonate group with specific parameters (P-C bond instead of P-O bond), which changes the metabolic stability parameter while maintaining reasonable structural complexity. The phosphonate group's unique chemical parameters allow it to resist phosphatase degradation while requiring only two phosphorylation steps to reach the active diphosphate form
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
These derivatives demonstrate potent antiviral activity by effectively inhibiting viral enzymes, offering a new approach to treating viral disorders, including HIV and hepatitis, with potential for improved therapeutic outcomes and reduced resistance.
Implementation Method 1
the discovery of the phosphonate as a stable isostere for the phosphate bond
Implementation Method 2
NRTIs disrupt viral replication through two distinct modes; competitive inhibition of HIV RT with respect to the dNTP substrate, and DNA chain termination
Data Source
AI summary
The present invention relates to a compound of formula (I), or a pharmaceutically acceptable salt or prodrug thereof, and their use in medicine particular as anti-viral agents;wherein:X is selected from O and NR11;Y is selected from O, S and NR12;A is selected from —(CR1R2)n-, —(CR9R10)—, —(CR9R10)—(CR1R2)n-, —(CR1R3)—(CR2R4)—(CR1R2)n-, —CR3═CR4—(CR1R2)n- and —C≡C—(CR1R2)n-;R1 and R2 are independently selected from H, alkyl, hydroxyl, hydroxymethyl and halogen;R3 and R4 are independently selected from H and alkyl, or R3 and R4 together with the carbon atoms to which they are attached form a mono or bicyclic ring system selected from cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl and heteroaryl;R5 is selected from H, P(═O)(OH)2 and P(═O)(OH)—O—P(═O)(OH)2;R6 is selected from H and alkyl;R7 and R8 are independently selected from H, alkyl, halogen and hydroxymethylR9 and R19 together with the carbon atoms to which they are attached form a mono or bicyclic ring system selected from cycloalkyl, cycloalkenyl, heterocycloalkyl and heterocycloalkenyl;R11 is selected from H and alkyl;R12 is selected from H and alkyl;m is 0, 1, 2 or 3;n is 1, 2 or 3;p is 0 or 1;q is 0, 1, 2 or 3;r is 0, 1, 2, 3, 4 or 5;s is 0 or 1;Base is a natural or non-natural nucleobase, andwherein each alkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl and heteroaryl may be optionally substituted as described herein.