Quinone-Based Nitric Oxide Donors for Vascular Disease Treatment
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Solution Overview
Problem
Classical organic nitrates used for treating vascular diseases exhibit nitrate tolerance and side effects such as headache, hypotension, and flush, limiting their clinical use due to reduced efficacy and increased sensitivity to vasoconstrictor substances.
Innovation Solution
Development of nitric oxide donor compounds with a specific chemical structure that provides extended release of NO, reducing nitrate tolerance and side effects, and can be administered through various routes including oral, parenteral, and transdermal methods.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If classical organic nitrates are used for treating vascular diseases, then vasodilating effect is achieved, but nitrate tolerance and side effects occur
Solution Approach 1:
The patent modifies the chemical structure of traditional nitrate compounds by replacing the nitrate group with alternative nitric oxide releasing groups (such as N-nitroso compounds, diazeniumdiolates, or S-nitroso compounds). This parameter change in molecular structure allows the compound to release NO through different biochemical pathways, thereby maintaining vasodilating efficacy while avoiding nitrate tolerance and associated side effects like headache and hypotension
Solution Approach 2:
The invention creates hybrid molecules that combine the quinone core structure with various nitric oxide releasing moieties. These composite structures integrate the pharmacological benefits of quinones with the NO-donating capabilities of alternative groups, producing compounds that exhibit both antioxidant properties and vasodilating effects without inducing nitrate tolerance
2Reliability
If continuous high doses of organic nitrates are administered, then therapeutic effect is maintained, but nitrate tolerance develops rapidly
Solution Approach 1:
The alternative NO-donating compounds exhibit sustained release characteristics that provide more consistent therapeutic levels over time. The molecular design allows for gradual NO release through enzymatic cleavage or chemical decomposition, creating a periodic action pattern that maintains efficacy without the rapid tolerance development seen with continuous high-dose nitrate administration
Solution Approach 2:
By changing the biochemical pathway of NO release from the traditional nitrate reductase-dependent mechanism to alternative pathways (such as chemically labile bonds or enzyme-independent decomposition), the patent extends the duration of therapeutic effect while preventing the adaptive responses that lead to tolerance
3Reliability
If organic nitrates are used to treat vascular diseases, then coronary dilatation and reduced preload/afterload occur, but rebound vasoconstriction and sensitivity to vasoconstrictors increase
Solution Approach 1:
The patent converts the harmful rebound vasoconstriction effect into a beneficial sustained vasodilatory response by using alternative NO-donating groups that release NO more gradually and through different mechanisms. This prevents the compensatory vasoconstrictor response that normally follows nitrate withdrawal, thereby eliminating the rebound effect while maintaining coronary dilatation and hemodynamic improvement
4Reliability
If traditional nitrate compounds are administered, then vasodilating activity is achieved, but unpleasant side effects such as headache, hypotension, and flush occur
Solution Approach 1:
The patent changes the molecular parameters of nitrate compounds by replacing the nitrate ester group with alternative NO-releasing groups that have different biochemical properties. This structural modification alters the mechanism of action to reduce excessive cerebral vasodilatation (causing less headache) and prevents excessive systemic vasodilation (reducing hypotension and flush), while maintaining beneficial coronary and peripheral vasodilating activity
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 compounds demonstrate improved pharmacological activity with reduced nitrate tolerance and side effects, effectively treating vascular diseases and conditions like pulmonary hypertension, and can be combined with other active ingredients for enhanced therapeutic benefits.
Implementation Method 1
nitric oxide donor compounds which can produce extended release of NO
Data Source
AI summary
The present invention relates to nitric oxide donor compounds having a quinone based structure, to processes for their preparation and to their use in the treatment of pathological conditions where a deficit of NO plays an important role in their pathogenesis.