Isosorbide Derivatives for Localized Nitric Oxide Release
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Solution Overview
Problem
Current treatments for cardiovascular diseases related to cellular hypoxia lack targeted and effective solutions, often causing side effects due to global modulation of hypoxia-mediated events, and there is a need for compounds that can potentiate vasodilatory release of nitric oxide (NO) in a localized manner to treat and prevent major adverse cardiac events.
Innovation Solution
Development of novel compounds that release nitrate and urea or urea analogues at the endothelial surface, which augment nitric oxide production by overcoming the upregulation of UT-B-mediated urea transport, facilitating vasodilation and ischemic preconditioning in areas of cellular hypoxia.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If prolyl hydroxylase inhibitors are used to potentiate HIF-mediated events, then hypoxia-related gene expression is enhanced, but side effects occur due to global modulation of hypoxia-mediated events
Solution Approach 1:
The patent applies local quality by designing compounds that selectively act in areas of cellular hypoxia rather than globally. The compounds are delivered to and activated specifically in hypoxic tissues, such as ischemic heart muscle, allowing localized potentiation of vasodilatory NO release without system-wide effects. This resolves the contradiction by maintaining therapeutic effectiveness in the target area while avoiding harmful side effects from global modulation.
Solution Approach 2:
The invention segments the hypoxia response into specific localized areas rather than treating it as a uniform global phenomenon. By delivering compounds specifically to ischemic regions and using tissue-specific delivery mechanisms, the therapy segments the action to only where needed, thereby improving reliability in treating cardiovascular diseases while minimizing harmful effects from widespread activation.
2Adaptability or versatility
If unfocused therapeutic agents are used to treat hypoxia-related conditions, then broad hypoxia-mediated events are modulated, but side effects increase due to lack of selectivity
Solution Approach 1:
The patent achieves local quality by creating compounds with selective delivery and activation properties. The molecules are designed to accumulate and activate specifically in hypoxic tissues through mechanisms such as hypoxia-induced uptake or localized metabolic activation, thereby maintaining adaptability to treat various hypoxia conditions while eliminating harmful side effects from non-selective action.
Solution Approach 2:
The invention uses intermediary mechanisms such as tissue-specific transporters or metabolic intermediaries to guide the compounds to hypoxic areas. These intermediaries act as mediators that enable selective delivery and activation only in the desired tissue context, allowing broad therapeutic applicability while preventing harmful effects from non-selective distribution.
3Reliability
If global approaches to hypoxia treatment are used, then system-wide hypoxia effects are addressed, but complexity of pathophysiology is underestimated and safety is compromised
Solution Approach 1:
The patent addresses local quality by focusing treatment on specific hypoxic tissues rather than attempting to manage all hypoxia effects system-wide. This localized approach simplifies the therapeutic strategy by targeting only the most critical and treatable areas, thereby improving safety profile while acknowledging and respecting the complexity of overall hypoxia pathophysiology through selective rather than comprehensive intervention.
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 locally alleviate hypoxia-induced effects, enhancing nitric oxide production and vasodilation, thereby treating cardiovascular diseases with reduced side effects compared to unfocused therapeutic agents, and providing targeted protection against ischemic events.
Implementation Method 1
These compounds are small molecules with a central isosorbide moiety attached to a urea moiety... and an opposing nitrate group... that respond to areas of cellular hypoxia... release nitrate in addition to urea or a urea analogue
Implementation Method 2
They are expected to provide a therapeutic response focused in areas of cellular hypoxia... enhancing nitric oxide production and vasodilation
Implementation Method 3
overcoming the upregulation of UT-B-mediated urea transport... UT-B (urea transport protein, B, the product of the gene SLC14A1) facilitates transport of urea, water and urea analogues across cell membranes
Implementation Method 4
facilitating vasodilation and ischemic preconditioning in areas of cellular hypoxia... enhancing nitric oxide production and vasodilation
Data Source
AI summary
The present invention provides novel compounds and pharmaceutical compositions thereof and methods of using the same for treating cardiovascular diseases.