Nucleoside Analog Prodrug Esterification for Oral Bioavailability
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Solution Overview
Problem
Current nucleoside analogs, such as β-d-N4-hydroxycytidine and GS-441524, exhibit limited oral bioavailability, making them unsuitable for development as effective oral antiviral drugs against viruses like SARS-CoV-2, influenza, and other viral infections.
Innovation Solution
Development of a nucleoside analog prodrug with improved pharmacokinetic properties, represented by formula I or its pharmaceutically acceptable salts, which enhances oral bioavailability and antiviral activity, specifically targeting coronaviruses, influenza viruses, and other viral infections.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If nucleoside analogs (such as β-d-N4-hydroxycytidine and GS-441524) are used as antiviral drugs, then antiviral activity is improved, but oral bioavailability deteriorates (less than 10% in monkeys)
Solution Approach 1:
The patent applies prodrug modification by introducing ester groups (such as acetate, formate, or other esterifying groups) as intermediary structures that improve oral bioavailability. These ester groups act as mediators that enhance absorption and metabolic properties, allowing the active nucleoside analog to be released in vivo after absorption, thus resolving the contradiction between antiviral activity and oral bioavailability
Solution Approach 2:
The patent modifies chemical parameters of the nucleoside analog by esterifying hydroxyl groups with various esterifying agents (such as acetic anhydride, formic acid, or other esters). This parameter change transforms the parent compound into prodrug forms with improved pharmacokinetic properties, including enhanced oral bioavailability while maintaining antiviral efficacy through in vivo conversion to the active form
Data Source
AI summary
The present invention relates to a nucleoside analog represented by the following formula and a use thereof. Specifically, the present invention relates to a nucleoside analog represented by the following formula or a pharmaceutically acceptable salt thereof, and a pharmaceutical composition thereof, and a use thereof in preparation of (a) an inhibitor for inhibiting replication of coronaviruses, paramyxoviruses, influenza viruses, flaviviruses, filoviruses, bunya viruses and/or arenaviruses, and/or (b) a medicine for treating and/or preventing or alleviating a disease caused by infection of coronaviruses, paramyxoviruses, influenza viruses, flaviviruses, filoviruses, bunya viruses and/or arenaviruses.