Bis-acylated Hydroxylamine Derivatives for Nitroxyl Therapy

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Solution Overview

Problem

Current therapies for conditions such as congestive heart failure, ischemia/reperfusion injury, and pulmonary hypertension have limitations, including adverse effects and inadequate responses in some patients, highlighting a need for alternative treatments that can effectively manage these diseases and improve patient outcomes.

Innovation Solution

Development of bis-acylated hydroxylamine derivative compounds that donate nitroxyl (HNO) under physiological conditions, which can be used to treat heart failure, ischemia/reperfusion injury, and pulmonary hypertension by modulating nitroxyl levels in the body.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If current therapies (vasodilators, positive inotropes, diuretics, beta-antagonists) are used to treat congestive heart failure, then cardiac function can be improved, but adverse effects and accelerated mortality rate occur

Engineering Contradiction:

Improvetreatment effectivenessVSAvoidadverse effects

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The patent changes the chemical parameter by introducing bis-acylated hydroxylamine derivatives with specific molecular structures that donate nitroxyl under physiological conditions. This chemical parameter change leads to a physiological parameter change (nitroxyl donation) that improves cardiac function without the adverse effects of conventional therapies.

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The patent introduces nitroxyl (HNO) as an intermediary substance that mediates the therapeutic effect. The bis-acylated hydroxylamine derivatives serve as prodrugs that release nitroxyl in vivo, which then acts as the active intermediary to improve cardiac function, reduce pulmonary arterial pressure, and protect against ischemia/reperfusion injury without the harmful side effects of conventional drugs.

Inventive Principle:

Principle #24Intermediary (Mediator)

2Strength

If positive inotropic agents (beta-adrenergic agonists) are used to increase heart contractility, then myocardial contractility is improved, but arrhythmogenesis and increased oxygen demand occur

Engineering Contradiction:

Improvemyocardial contractilityVSAvoidarrhythmogenesis

Core Design Contradiction:

StrengthVSObject-affected harmful factors

Solution Approach 1:

The patent converts the harmful approach of directly stimulating beta-adrenergic receptors (which causes arrhythmogenesis) into a beneficial approach by using nitroxyl donation to achieve the same therapeutic goal (improved contractility) through a different mechanism that does not provoke arrhythmias. The nitroxyl acts as a beneficial intermediary that improves contractility without the harmful side effects.

Inventive Principle:

Principle #22Blessing in disguise (Convert harm into benefit)

3Reliability

If beta-antagonists are used to treat heart failure, then mortality and morbidity are reduced, but the mechanism of action of positive inotropic beta-agonists is blocked

Engineering Contradiction:

Improvemortality reductionVSAvoidtreatment flexibility

Core Design Contradiction:

ReliabilityVSAdaptability or versatility

Solution Approach 1:

The patent creates a universal therapeutic agent (nitroxyl-donating compounds) that can address multiple therapeutic needs simultaneously. These compounds can improve cardiac function, reduce pulmonary arterial pressure, and protect against ischemia/reperfusion injury through a single mechanism (nitroxyl donation), providing treatment versatility that is not limited by beta-receptor blockade.

Inventive Principle:

Principle #6Universality (Multi-functionality)

4Stress or pressure

If conventional therapies are used for pulmonary hypertension, then blood pressure can be reduced, but inadequate response occurs in some patients

Engineering Contradiction:

Improvepulmonary arterial pressureVSAvoidtreatment response

Core Design Contradiction:

Stress or pressureVSReliability

Solution Approach 1:

The patent introduces a new chemical parameter (nitroxyl donation) that leads to physiological changes (vasodilation and improved cardiac function) effective in reducing pulmonary arterial pressure. This approach provides an alternative mechanism that may be effective in patients who do not respond adequately to conventional therapies.

Inventive Principle:

Principle #35Parameter changes

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

These compounds demonstrate potential in improving cardiac function, reducing tissue damage from ischemia/reperfusion, and lowering pulmonary arterial pressure, thereby enhancing treatment options for these conditions.

Implementation Method 1

Development of bis-acylated hydroxylamine derivative compounds that donate nitroxyl (HNO) under physiological conditions

Methodology Applied

Scientific EffectNitroxyl donation:

Data Source

PatentUS9458127B2Bis-acylated hydroxylamine derivatives

Publication Date: 2016.10.04 JOHNS HOPKINS UNIVERSITY

AI summary

The invention provides certain bis-acylated hydroxylamine derivative compounds, pharmaceutical compositions and kits comprising such compounds, and methods of using such compounds or pharmaceutical compositions. In particular, the invention provides methods of using such compounds or pharmaceutical compositions for treating, preventing, or delaying the onset and/or develop of a disease or condition. In some embodiments, the disease or condition is selected from cardiovascular diseases, ischemia, reperfusion injury, cancerous disease, pulmonary hypertension and conditions responsive to nitroxyl therapy.