Relebactam Prodrugs for Oral Bioavailability
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Solution Overview
Problem
The emergence of resistant bacteria due to overuse and misuse of antibiotics limits the effectiveness of conventional β-lactam antibiotics, as these bacteria express β-lactamases that degrade the antibiotics, necessitating a solution to inhibit β-lactamases effectively.
Innovation Solution
Development of pharmaceutical compositions containing derivatives of relebactam, specifically compounds with defined structural formulas, which can be administered orally to inhibit β-lactamases and enhance the efficacy of β-lactam antibiotics by forming pharmaceutically acceptable salts or compositions with a pharmaceutically acceptable vehicle.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If relebactam is administered intravenously, then therapeutic effectiveness against resistant bacteria is achieved, but convenience and ease of administration deteriorate
Solution Approach 1:
The patent changes the administration parameter from intravenous to oral by modifying relebactam into prodrugs with specific ester groups (carboxylate, sulfonate, or phosphate esters). This parameter change enables oral bioavailability while maintaining therapeutic effectiveness, directly resolving the contradiction between effectiveness and ease of administration.
Solution Approach 2:
The patent introduces prodrug intermediaries that serve as carriers for relebactam. These prodrugs (compounds of Formula 1) act as intermediaries that facilitate oral administration and release active relebactam in the body, thereby improving ease of administration while preserving therapeutic effectiveness.
2Productivity
If conventional β-lactam antibiotics are used, then bacterial infections are treated, but effectiveness deteriorates due to β-lactamase degradation
Solution Approach 1:
The patent applies preliminary anti-action by introducing β-lactamase inhibitor groups (such as avibactam, relebactam, or other inhibitors) into the antibiotic molecule before administration. This preliminary inhibition of β-lactamases prevents degradation of the β-lactam ring, thereby maintaining antibiotic efficacy and reliability against resistant bacteria.
Solution Approach 2:
The patent creates composite molecular structures combining β-lactam antibiotics with β-lactamase inhibitor groups. These composite molecules (conjugates or prodrugs) simultaneously provide antibiotic activity and β-lactamase inhibition, resolving the contradiction between productivity and reliability.
3Ease of operation
If oral administration is used, then convenience and bioavailability are improved, but formulation complexity increases
Solution Approach 1:
The patent changes the chemical parameters of relebactam by introducing specific ester groups (carboxylate, sulfonate, phosphate) that enable oral stability and bioavailability. These parameter changes in the molecular structure allow oral administration without requiring complex formulation systems, thus improving ease of operation while minimizing formulation complexity.
Data Source
Figure 1
AI summary
Derivatives of relebactam, therapeutic methods of using the derivatives of relebactam, particularly in combination with β -lactam antibiotics and pharmaceutical compositions thereof are disclosed. The derivatives of relebactam are suitable for oral administration.