Valsartanamide Dinitrate Sequential Nitric Oxide Release
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Solution Overview
Problem
Current treatments for vascular and metabolic diseases, such as hypertension and atherosclerosis, often lead to nitrate tolerance and vascular dysfunction due to the short half-life of nitrate esters, necessitating frequent dosing and adverse effects like oxidative stress.
Innovation Solution
Development of dinitrate esters of valsartanamide derivatives with nitrate functions attached to both the tetrazole unit and the amide substituent, which release nitrogen monoxide sequentially, enhancing vasodilatory potency and reducing oxidative stress.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Speed
If organic nitrates with short half-life are used for treatment, then fast-acting vasodilation effect is achieved, but nitrate tolerance develops requiring frequent dosing
Solution Approach 1:
The patent combines two nitrate ester groups onto the valsartanamide molecule to create a dinitrate derivative. This merging of multiple nitrate functions into a single molecular entity allows for sustained NO release over time, extending the duration of action while maintaining the fast-acting vasodilatory effect characteristic of nitrate esters.
Solution Approach 2:
The invention creates a composite molecular structure by attaching nitrate ester groups to the valsartanamide scaffold. This composite approach integrates the angiotensin II receptor blocking activity of valsartan with the vasodilatory properties of nitrate esters, producing a compound with both prolonged duration and enhanced pharmacodynamic effects.
2Reliability
If conventional nitrate esters are used chronically, then vasodilatory effect is maintained, but oxidative stress and vascular dysfunction occur
Solution Approach 1:
The patent converts the potentially harmful rapid release of NO from conventional nitrates into a beneficial controlled sequential release pattern. The dinitrate structure allows for staged NO release, preventing the oxidative stress and vascular dysfunction associated with conventional nitrate esters while maintaining therapeutic vasodilatory effects.
3Reliability
If frequent dosing is administered to overcome nitrate tolerance, then therapeutic effect is maintained, but treatment complexity increases
Solution Approach 1:
The dinitrate derivative provides excessive NO release capacity compared to conventional mononitrates, with sequential release from two nitrate ester groups. This excessive action ensures sustained therapeutic effect throughout the dosing interval, allowing for less frequent dosing while maintaining reliable vasodilatory and antihypertensive effects.
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 dinitrate esters of valsartanamide demonstrate superior vasodilatory properties compared to valsartan and other nitrate esters, with reduced risk of nitrate tolerance and oxidative stress, effectively managing vascular and metabolic diseases with improved pharmacodynamic effects.
Implementation Method 1
dinitrate esters of valsartanamide derivatives with nitrate functions attached to both the tetrazole unit and the amide substituent, which release nitrogen monoxide sequentially
Data Source
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AI summary
A dinitrate ester of a valsartanamide is described. It has superior properties in the treatment of vascular and metabolic diseases.