Intramolecular Cyclization-elimination for Controlled HNO Release
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Solution Overview
Problem
Current nitroxyl (HNO) donors are limited in number and effectiveness for treating cardiovascular diseases, particularly for failing hearts, due to their inherent reactivity, with few physiologically useful compounds beyond Angeli's salt and derivatives like Piloty's acid and acyloxy nitroso compounds.
Innovation Solution
Development of new compounds capable of intramolecular cyclization-elimination at neutral pH to non-enzymatically release HNO, specifically designed as HNO donors with structures that allow controlled release and modulation of nitroxyl levels in vivo, including specific structures and combinations with other therapeutic agents.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Adaptability or versatility
If existing HNO donors (Angeli's salt, Piloty's acid derivatives, acyloxy nitroso compounds) are used, then HNO can be delivered to treat cardiovascular diseases, but the number of available compounds is limited and their physiological usefulness is restricted
Solution Approach 1:
The patent segments the HNO donor function into a modular structure consisting of a nitroxyl precursor moiety and a trigger moiety connected by a linker. This segmentation allows independent optimization of each component and enables combinatorial chemistry to generate diverse HNO donor compounds with different release characteristics and physiological properties
Solution Approach 2:
The patent employs parameter changes by modifying the trigger moiety to respond to physiological pH conditions (pH 7.4), changing the release mechanism from requiring acidic or enzymatic conditions to pH-triggered release. This parameter change expands the physiological usefulness of HNO donors by enabling release under normal physiological conditions without requiring acidic environments or specific enzymes
2Reliability
If HNO is generated in situ through prodrugs, then the reactivity of HNO is managed, but very few physiologically useful HNO donors exist beyond the known classes
Solution Approach 1:
The patent creates a universal HNO donor platform that can function through multiple mechanisms. The prodrug contains both a nitroxyl precursor and a pH-sensitive trigger moiety that can undergo cyclization-elimination to release HNO. This universal structure can accommodate various nitroxyl precursors and triggers, enabling one platform to serve multiple functions and generate diverse classes of donors
Solution Approach 2:
The patent constructs composite HNO donor molecules by combining a nitroxyl precursor moiety with a trigger moiety through a linker. This composite structure integrates the HNO-releasing capability of the precursor with the pH-sensitivity of the trigger, creating a new class of compounds that combine properties of both components to achieve controlled release
3Adaptability or versatility
If intramolecular cyclization-elimination is used for HNO release, then non-enzymatic release at neutral pH is achieved, but the compound structure must be specifically designed with appropriate linkers and triggers
Solution Approach 1:
The patent implements self-service by designing the HNO donor prodrug to automatically undergo intramolecular cyclization-elimination at physiological pH without requiring external enzymes or catalysts. The trigger moiety is designed to spontaneously cyclize and eliminate HNO when exposed to pH 7.4 conditions, enabling the compound to serve itself and release HNO autonomously in the physiological environment
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 effectively modulate in vivo nitroxyl levels, providing therapeutic benefits for cardiovascular diseases such as congestive heart failure and myocardial ischemia/reperfusion injury, offering improved treatment options compared to existing HNO donors.
Implementation Method 1
compounds that are capable of undergoing intramolecular cyclization-elimination at a neutral pH under physiological conditions to non-enzymatically release or donate HNO
Data Source
AI summary
Protected HNO donors designed to undergo non-enzymatic release at neutral pH via an intramolecular cyclization-elimination are disclosed. The rate of cyclization, and therefore HNO release, can be controlled by substituents and chain length. Thus, biologically useful HNO donors having tunable HNO release rates are provided.