Soluble Guanylate Cyclase Activators Tolerant to Nitrate Effects
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Solution Overview
Problem
Current pharmacological stimulation of soluble guanylate cyclase (sGC) for treating disorders associated with low cGMP levels, such as hypertension and atherosclerosis, faces challenges like development of tolerance and reduced activity over time, and existing compounds have weak effects on cGMP formation.
Innovation Solution
Development of specific compounds, including 2-sulfonylaminobenzoic acid N-arylamides and pyrazoles, that strongly activate soluble guanylate cyclase, modulating cGMP production to treat cardiovascular diseases and related disorders.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If organic nitrates are used for pharmacological stimulation of sGC, then sGC activation is achieved, but tolerance develops and activity reduces over time
Solution Approach 1:
The patent changes the chemical structure parameters of sGC stimulators by introducing specific heterocyclic rings (pyrazole, triazole, tetrazole) with electron-withdrawing groups at defined positions, creating compounds with optimized binding affinity and reduced tolerance development while maintaining sustained activation efficacy
Solution Approach 2:
The invention combines multiple structural elements into composite molecules: a core heterocyclic ring system with specific substituents (electron-withdrawing groups at positions 1 and 5), creating a multi-component molecular structure that achieves both potent sGC activation and reduced tolerance compared to simple organic nitrates
2Reliability
If existing sGC stimulators are used, then some sGC activation occurs, but the effect on cGMP formation is weak
Solution Approach 1:
The patent optimizes molecular parameters by introducing strong electron-withdrawing groups (trifluoromethyl, cyano, halo substituents) at specific positions of the heterocyclic ring system, which enhances the electronic properties and binding affinity to sGC, thereby dramatically increasing cGMP formation rate and potency compared to existing stimulators
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 activate sGC, leading to enhanced cGMP production, providing therapeutic benefits for conditions like hypertension, angina pectoris, and atherosclerosis with improved efficacy and reduced tolerance issues.
Implementation Method 1
The soluble guanylate cyclases ('sGC'), which are cytosolic heterodimeric heme proteins, in contrast, are essentially regulated by a family of low-molecular-weight factors which are formed enzymatically
Implementation Method 2
The binding of NO to the heme with formation of a penta-coordinate heme-nitrosyl complex is proposed as the mechanism of the activation by NO
Data Source
AI summary
A compound having the structure I useful for treatment or prevention of cardiovascular diseases, endothelial dysfunction, diastolic dysfunction, atherosclerosis, hypertension, angina pectoris, thromboses, restenoses, myocardial infarction, strokes, cardiac insufficiency, pulmonary hypertonia, erectile dysfunction, asthma bronchiale, chronic kidney insufficiency, diabetes, or cirrhosis of the liver in a human or animal patient.