Isosorbide Urea Nitrate Compounds for Targeted Hypoxic Vasodilation
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Solution Overview
Problem
Current treatments for cardiovascular diseases related to cellular hypoxia lack targeted and effective approaches, often leading to 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 hypoxic conditions to prevent major adverse cardiac events.
Innovation Solution
Development of novel compounds with a central isosorbide moiety attached to a urea or glycolamide moiety and a nitrate group, which facilitate the release of urea or urea analogues and nitrate at the endothelial surface, enhancing nitric oxide production and vasodilation, thereby enabling ischemic preconditioning in a targeted manner.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If prolyl hydroxylase inhibitors are used to potentiate HIF and treat hypoxia-related conditions, then angiogenesis and red blood cell development are improved, but side effects occur due to global modulation of hypoxia-mediated events affecting multiple organs and systems
Solution Approach 1:
The patent applies local quality by designing compounds that selectively target hypoxia-mediated events in specific tissues (heart, vascular endothelium) rather than systemically. The compounds are formulated to accumulate in ischemic myocardium and vascular beds, providing localized HIF modulation only where hypoxia is present, thereby avoiding widespread side effects while maintaining therapeutic efficacy in the affected organ.
Solution Approach 2:
The patent segments the hypoxia response pathway by targeting specific downstream effectors (COX-2, eNOS, UT-B) rather than using global HIF modulators. This segmentation allows independent control of different hypoxia-mediated processes in different tissues, enabling therapeutic intervention in the heart while leaving other systems unaffected.
2Reliability
If global HIF potentiation is used to treat cardiovascular hypoxia, then blood vessel growth to hypoxic regions is improved, but arterial supply to dormant malignancies increases and cell metabolism is altered to conserve oxygen
Solution Approach 1:
The compounds are designed to locally potentiate HIF only in ischemic cardiovascular tissues through selective accumulation in the heart and vascular beds. This localized action promotes angiogenesis in hypoxic cardiac regions while avoiding the arterial supply increase that would benefit dormant malignancies elsewhere in the body.
Solution Approach 2:
The patent uses tissue-specific intermediaries (cardioselective transport mechanisms, local metabolic enzymes) to ensure that HIF potentiation occurs only in the intended therapeutic target. The compounds leverage existing tissue transporters and metabolic pathways to achieve selective delivery and activation in the heart, preventing systemic effects that would inadvertently support tumor growth.
3Reliability
If repetitive brief hypoperfusion and reperfusion is used for preconditioning, then tolerance to future ischemic events is improved, but the complexity of treatment protocols increases
Solution Approach 1:
The compounds provide endogenous preconditioning protection by being activated within the ischemic tissue itself. The compounds accumulate in hypoxic regions and provide sustained protection against ischemic injury without requiring external control of perfusion cycles. This self-contained mechanism eliminates the need for complex monitored hypoperfusion-reperfusion protocols while maintaining the protective effect.
Solution Approach 2:
The patent replaces the mechanical control system of repetitive hypoperfusion-reperfusion cycles with a biochemical mechanism. Instead of mechanically controlling blood flow patterns to achieve preconditioning, the compounds provide a chemical mediator that induces and maintains protective metabolic states within the tissue, simplifying the treatment approach while preserving the preconditioning effect.
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 potentiate NO production and vasodilation in hypoxic conditions, reducing vascular tone and providing therapeutic benefits for cardiovascular diseases with minimal side effects by focusing treatment on areas of cellular hypoxia, thus addressing the limitations of existing therapies.
Implementation Method 1
Compounds useful for treating cardiovascular diseases include nitrate and/or urea or a urea analogue releasing agents, and/or nitric oxide (NO) donors
Implementation Method 2
enhancing nitric oxide production and vasodilation
Implementation Method 3
These compounds effectively potentiate NO production and vasodilation in hypoxic conditions, reducing vascular tone
Data Source
AI summary
The present invention provides novel compounds and pharmaceutical compositions thereof and methods of using the same for treating cardiovascular diseases.