Asymmetrical Neuromuscular Blocking Agents with Cysteine Reversal

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Solution Overview

Problem

Current neuromuscular blocking agents have limitations such as slow recovery from intermediate-duration agents requiring antagonist administration, deep blockade duration, and undesirable side effects like cardiac arrhythmias and histamine release, along with variable metabolism and prolonged blockade due to abnormal pseudocholinesterase levels.

Innovation Solution

Development of neuromuscular blocking agents with a specific formula that allows for reversible neuromuscular blockade using cysteine or related compounds, providing a kit with the agent and antagonist for inducing and reversing neuromuscular blockade, minimizing side effects and improving recovery times.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Duration of action of moving object

If intermediate-duration neuromuscular blocking agents are used, then muscle relaxation is maintained during surgery, but recovery is slow and requires antagonist administration

Engineering Contradiction:

Improveduration of neuromuscular blockadeVSAvoidrecovery time

Core Design Contradiction:

Duration of action of moving objectVSLoss of time

Solution Approach 1:

The patent divides the neuromuscular blocking agent into two distinct molecular components: a steroidal portion and a non-steroidal portion connected by a linker. This segmentation allows the steroidal portion to provide prolonged muscle relaxation while the non-steroidal portion enables rapid reversal by pseudocholinesterase, resolving the contradiction between maintaining duration and enabling quick recovery

Inventive Principle:

Principle #1Segmentation

Solution Approach 2:

The invention extracts the reversible portion from traditional short-acting agents and combines it with intermediate-acting steroidal agents. The non-steroidal portion is designed to be specifically cleaved by pseudocholinesterase, allowing the blocking effect to be divided into a permanent steroidal component and a removable non-steroidal component, enabling controlled reversal

Inventive Principle:

Principle #2Taking out (Extraction)

2Speed

If high dosage of intermediate-duration agents is given for fast intubation, then tracheal intubation is facilitated within 60-90 seconds, but blockade duration is prolonged to one to three hours

Engineering Contradiction:

Improveonset speed of neuromuscular blockadeVSAvoidduration of neuromuscular blockade

Core Design Contradiction:

SpeedVSDuration of action of moving object

Solution Approach 1:

The patent applies local quality by making different portions of the molecule serve different temporal functions. The steroidal portion provides the prolonged blocking effect for sustained muscle relaxation, while the non-steroidal portion is specifically designed for rapid metabolism. This allows the agent to produce fast onset at lower doses without proportionally extending the total blockade duration, as the non-steroidal portion can be quickly removed

Inventive Principle:

Principle #3Local quality

3Speed

If short and ultra-short acting agents are used, then fast onset facilitates early intubation, but blockade is markedly prolonged when pseudocholinesterase is abnormal

Engineering Contradiction:

Improveonset speed of neuromuscular blockadeVSAvoidpredictability of blockade duration

Core Design Contradiction:

SpeedVSReliability

Solution Approach 1:

The patent creates an asymmetrical molecular structure where the steroidal portion and non-steroidal portion have fundamentally different metabolic fates. The steroidal portion resists pseudocholinesterase metabolism providing stable, predictable baseline blockade, while the non-steroidal portion is specifically designed to be cleaved by pseudocholinesterase. This asymmetry ensures that even when pseudocholinesterase activity varies, the steroidal core maintains reliable blockade while the non-steroidal portion can still be removed, preventing marked prolongation

Inventive Principle:

Principle #4Asymmetry

4Speed

If succinylcholine is used for fast intubation, then tracheal intubation is facilitated within 60 seconds, but undesirable side effects occur such as cardiac arrhythmias and muscle pain

Engineering Contradiction:

Improveonset speed of neuromuscular blockadeVSAvoidside effects including cardiac arrhythmias and muscle pain

Core Design Contradiction:

SpeedVSObject-generated harmful factors

Solution Approach 1:

The patent merges the fast-onset properties of short-acting agents with the safety profile of intermediate-acting agents. By combining the steroidal portion (which provides safe, controllable blockade without succinylcholine's side effects) with a non-steroidal portion designed for rapid cleavage, the invention achieves fast onset comparable to succinylcholine while eliminating its harmful effects. The hybrid structure allows rapid metabolism without triggering cardiac arrhythmias or muscle pain

Inventive Principle:

Principle #5Merging (Combining)

Data Source

PatentEP2867219B1Asymmetrical reversible neuromuscular blocking agents of ultra-short, short, or intermediate duration

Publication Date: 2017.02.15 CORNELL UNIVERSITY

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AI summary

We describe ultra-short, short, and intermediate duration neuromuscular blocking compounds, reversible by cysteine or similar compounds, that are bisquatemary diesters of chlorofumaric, fumaric, or maleic acids where the quaternary groups are very different, creating a highly asymmetrical molecule where one quaternary includes an isoquinolinium ring system and the other includes a morpholinium, piperidinium, piperazinium, or pyrrolidinium system, pharmaceutical compositions, methods to use such compounds and compositions, and kits.