Elastase Inhibitor Prodrug for Extended Lung Exposure and Half-Life
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Current elastase inhibitors, such as Compound 52, suffer from short pulmonary exposure and rapid elimination, limiting their efficacy in treating chronic lung diseases like COPD.
Innovation Solution
Development of prodrugs with specific chemical structures, including compounds of formula I or their pharmaceutically acceptable salts, esters, isomers, solvates, or isotopically labeled compounds, designed to enhance pulmonary exposure and half-life.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If current elastase inhibitors (e.g., Compound 52) are used, then elastase activity is inhibited, but pulmonary exposure is short and elimination is rapid
Solution Approach 1:
The patent applies preliminary action by converting the active elastase inhibitor into a prodrug form that is administered first. The prodrug (compound of formula I) is metabolized in the body to release the active compound (Compound 52), thereby extending the duration of pulmonary exposure. This preliminary transformation allows the active inhibitor to be generated sustainably in the lungs, addressing the short exposure duration problem while maintaining reliable elastase inhibition.
2Reliability
If current elastase inhibitors are used, then elastase activity is inhibited, but half-life is short
Solution Approach 1:
The patent uses an intermediary approach by introducing a prodrug molecule as a mediator between administration and active inhibition. The prodrug (compound of formula I) serves as an intermediary that is more stable and has extended half-life characteristics. Upon administration, it is gradually converted to the active Compound 52, thereby extending the effective half-life of the elastase inhibition therapy while maintaining reliable efficacy.
3Duration of action of moving object
If prodrugs of formula I are used, then pulmonary exposure and half-life are increased, but molecular complexity increases
Solution Approach 1:
The patent applies parameter changes by systematically modifying the chemical parameters of the parent compound (Compound 52) to create the prodrug (formula I). Specific structural parameters are adjusted by introducing substitutable groups at defined positions (R1-R6, n, X, Y, Z) to optimize pulmonary exposure and half-life. This structured parameter modification approach extends duration of action while controlling complexity through systematic chemical design rather than random structural elaboration.
Data Source
AI summary
The present disclosure provides an elastase inhibitor prodrug and use thereof, being a compound of formula I or a pharmaceutically acceptable salt, ester, isomer or solvate thereof, prodrugs or isotopically labeled compound. Compared with the compound 52 (control example) in WO 2018/175173 A1, the compound disclosed herein has the advantages of high pulmonary exposure and long half-life. The prodrugs of the present disclosure significantly increase the concentration and residence time of the active compound (control example) in the lungs with significant improvements in pharmacokinetics in vivo compared to the control example.