Etomidate Analogues with Metabolically-Labile Esters
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Solution Overview
Problem
Current anesthetics, such as etomidate, pose a risk of adrenocortical suppression, making them unsafe for critically ill patients, particularly those with sepsis, due to their potent inhibition of adrenocortical function, and their pharmacokinetic profiles are difficult to predict across species.
Innovation Solution
Development of etomidate analogues with metabolically-labile ester moieties that are rapidly hydrolyzed, reducing adrenocortical suppression and extending the duration of action, while maintaining anesthetic potency and minimal cardiovascular effects.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If etomidate is used as an anesthetic agent, then hemodynamic stability is maintained, but adrenocortical function is potently inhibited
Solution Approach 1:
The patent extracts the harmful adrenocortical inhibition property from etomidate by removing the imidazole ring nitrogen atom (replacing with CH2), while preserving the beneficial hemodynamic stability and anesthetic potency through the core phenylethyl structure
Solution Approach 2:
The patent changes the chemical structure parameter by replacing the nitrogen atom in the imidazole ring with a CH2 group, creating a carbocyclic analogue that fundamentally alters adrenocortical interaction while maintaining anesthetic properties
2Duration of action of moving object
If esterase activity is increased to reduce drug duration, then metabolic stability improves, but pharmacokinetic profile becomes unpredictable across species
Solution Approach 1:
The patent changes the ester group parameters (R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12) to create analogues with optimized metabolic stability that falls within the optimal range for clinical use, balancing duration of action with species-independent pharmacokinetics
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 etomidate analogues provide a safer anesthetic option with reduced adrenocortical inhibition and improved pharmacokinetic properties, allowing for effective anesthesia with shorter duration of side effects and increased therapeutic index.
Implementation Method 1
etomidate analogues with metabolically-labile ester moieties that are rapidly hydrolyzed
Data Source
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AI summary
Provided herein are compounds according to formula (I): Provided herein is also a pharmaceutical composition comprising a compound according to formula (I) and a pharmaceutically acceptable carrier, and a method for providing anesthesia in a subj ect by administering such a pharmaceutical composition.