Dual-Functional NO Donor PDE4 Compounds for ARDS Treatment
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Solution Overview
Problem
Existing treatments for acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are limited in efficacy, particularly for conditions caused by infections, trauma, or viral diseases like COVID-19, due to the short half-life of nitric oxide and the limitations of inhaled NO, which can cause vasculature injury and inflammation.
Innovation Solution
Development of dual-functional compounds that continuously release nitric oxide (NO) and inhibit phosphodiesterase (PDE) activity, specifically targeting PDE4, to improve microcirculation, reduce inflammation, and enhance endothelium repair, using organic nitrates and PDE inhibitors like apremilast as core scaffolds.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Duration of action of moving object
If inhaled nitric oxide is used to treat ARDS, then acute respiratory distress can be relieved, but the short half-life causes limited efficacy and requires continuous administration
Solution Approach 1:
The patent applies preliminary action by incorporating nitric oxide donor groups directly into the apremilast molecule structure before administration. This pre-loading of NO groups ensures continuous NO release at the target site, eliminating the need for continuous external NO administration and extending the effective duration of action while maintaining reliable therapeutic effects.
2Object-affected harmful factors
If inhaled nitric oxide is used to treat ARDS, then respiratory distress can be relieved, but vasculature injury and inflammation occur as side effects
Solution Approach 1:
The patent applies local quality by designing the compound to release nitric oxide specifically at the lung tissue level where PDE4 inhibition is needed, rather than systemic circulation. The apremilast-NO conjugate targets pulmonary tissues selectively, providing local NO therapy that relieves respiratory distress without causing systemic vasculature injury and inflammation associated with conventional inhaled NO.
3Adaptability or versatility
If conventional PDE4 inhibitors like apremilast are used, then inflammation can be reduced, but the therapeutic window is limited and tissue penetration is insufficient
Solution Approach 1:
The patent applies composite materials by creating a hybrid molecule that combines apremilast (PDE4 inhibitor) with nitric oxide donor groups. This composite structure integrates two therapeutic functions: PDE4 inhibition for anti-inflammatory effects and NO release for vasodilation and endothelium protection. The dual functionality expands the therapeutic window while enhanced lipophilicity improves tissue penetration capability, overcoming the limitations of conventional single-function agents.
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 provide a broader therapeutic window with enhanced tissue penetration and reduced side effects, effectively treating ARDS and related disorders by improving microcirculation, reducing inflammation, and promoting endothelium repair.
Implementation Method 1
compounds capable of releasing nitric oxide (NO) and inhibiting activity of a phosphodiesterase (PDE)
Implementation Method 2
inhibiting activity of a phosphodiesterase (PDE), specifically targeting PDE4
Data Source
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AI summary
The present disclosure provides a compound configured to release nitric oxide (NO) and inhibit the activity of a phosphodiesterase (PDE) when administered to a subject. The compound may include L1 and L2. L1 may include a functional group that is part or all of a NO releasing agent. L2 may include a functional group that is part or all of a PDE inhibitor. The compound may further include a bond or a biradical that connects L1 and L2. The present disclosure further provides a method of treating or preventing a disease using the compound or a composition including the compound.