Pro-drug Controlled Release via Intramolecular Cyclization

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Solution Overview

Problem

Pro-drugs for biologically active compounds lack control mechanisms to prevent accidental overdosing or abuse, as they can be easily converted to the active drug through inappropriate routes or chemical modifications.

Innovation Solution

A pro-drug design featuring a hydrogen atom bonded to an aryloxy, arylthio, or arylamino group, where the hydrogen is substituted with an acyl leaving group bearing a nitrogen nucleophile protected with a proton or enzymatically-cleavable moiety, including an electron-withdrawing substituent, facilitating controlled release through intramolecular cyclization upon deprotonation or enzymatic cleavage.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If a pro-drug is designed for controlled release, then the reliability of treatment is improved, but the device complexity increases due to the need for enzymatic cleavage mechanisms

Engineering Contradiction:

Improvecontrolled releaseVSAvoidpro-drug structure

Core Design Contradiction:

ReliabilityVSDevice complexity

Solution Approach 1:

The pro-drug is segmented into distinct functional components: a biologically active compound, a linker containing a nitrogen nucleophile, and an enzymatically-cleavable moiety. This segmentation allows each component to perform its specific function while maintaining overall controlled release capability.

Inventive Principle:

Principle #1Segmentation

Solution Approach 2:

The nitrogen nucleophile acts as an intermediary that mediates between the biologically active compound and the enzymatically-cleavable moiety. It facilitates controlled release through intramolecular cyclization after enzymatic cleavage, ensuring reliable drug delivery while managing structural complexity.

Inventive Principle:

Principle #24Intermediary (Mediator)

2Ease of manufacture

If the nitrogen nucleophile is protected with a proton, then the ease of manufacture is improved, but the basicity of the nitrogen increases making it more susceptible to protonation at physiological pH

Engineering Contradiction:

Improveacid addition salt formationVSAvoidcyclization-release reaction

Core Design Contradiction:

Ease of manufactureVSReliability

Solution Approach 1:

The basicity of the nitrogen nucleophile is modified by introducing electron-withdrawing substituents (such as fluorine atoms) at the beta position. This parameter change reduces protonation susceptibility at physiological pH while maintaining the ability to form acid addition salts for easier manufacture and storage.

Inventive Principle:

Principle #35Parameter changes

3Object-affected harmful factors

If the pro-drug requires enzymatic cleavage for activation, then the susceptibility to abuse is reduced, but the duration of action increases due to the enzymatic cleavage step

Engineering Contradiction:

Improveabuse resistanceVSAvoidrelease time

Core Design Contradiction:

Object-affected harmful factorsVSDuration of action of moving object

Solution Approach 1:

The pro-drug is designed with pre-positioned enzymatically-cleavable moieties that are strategically placed to enable controlled release. The electron-withdrawing substituents are pre-installed at beta positions to facilitate rapid cyclization after enzymatic cleavage, optimizing both abuse resistance and release kinetics.

Inventive Principle:

Principle #10Preliminary action

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 pro-drug provides controlled release of the biologically active compound at physiological pH, reducing susceptibility to accidental overdosing or abuse, ensuring safe and effective treatment by requiring enzymatic cleavage for activation, thus preventing excessive plasma levels if administered inappropriately.

Implementation Method 1

the nitrogen nucleophile is capable of liberating the compound from the acyl leaving group by an intramolecular cyclization-release reaction

Methodology Applied

Scientific EffectIntramolecular cyclization: Chemical Bonding

Implementation Method 2

The presence of the electron-withdrawing substituent lowers the basicity of the nitrogen nucleophile, such that it is less susceptible to protonation at physiological pH

Methodology Applied

Scientific EffectInductive effect:

Implementation Method 3

the nitrogen nucleophile is protected with a proton or an enzymatically-cleavable moiety... upon deprotonation or enzymatic cleavage of the cleavable moiety

Methodology Applied

Scientific EffectEnzymatic cleavage: Enzyme

Data Source

PatentUS9023860B2Pro-drugs for controlled release of biologically active compounds

Publication Date: 2015.05.05 SIGNATURE THERAPEUTICS INC

AI summary

Pro-drugs containing an electron withdrawing substituent, as defined in the specification, are useful in a method for providing a patient with post administration-activated, controlled release of a biologically active compound.