Pyrazole Carboxylic Acid Derivatives for sGC Activation
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Solution Overview
Problem
Current pharmacological treatments for disorders associated with low cGMP levels, such as hypertension and endothelial dysfunction, face challenges like tolerance development and reduced efficacy over time, and existing sGC stimulators often have weak effects or require higher dosages.
Innovation Solution
Development of specific compounds, including 2-sulfonylaminobenzoic acid N-arylamides with thio substituents, that strongly activate soluble guanylate cyclase (sGC) to modulate cGMP production, offering a therapeutic and prophylactic approach for cardiovascular diseases and other conditions.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If organic nitrates are used to stimulate sGC, then cGMP production is increased, but tolerance develops and activity is reduced over time
Solution Approach 1:
The patent changes the chemical structure parameters of sGC stimulators by introducing specific substituents (halogens, cyano, nitro groups) at defined positions on the aromatic ring and pyridine moiety. This structural modification creates compounds with enhanced potency and altered pharmacokinetic properties that prevent tolerance development while maintaining sustained cGMP elevation.
Solution Approach 2:
The invention combines multiple functional groups (halogen atoms, cyano groups, nitro groups, pyridine ring, and aromatic substituents) into a composite molecular structure. This composite approach creates a synergistic effect where each substituent contributes to overall efficacy, allowing sustained activity without tolerance induction.
2Reliability
If existing sGC stimulators are used, then some cGMP formation stimulation is achieved, but the effects are weak and higher dosages are required
Solution Approach 1:
The patent optimizes molecular parameters by precisely positioning substituents at specific locations (e.g., halogen at position 2, cyano at position 5, nitro at position 4) on the aromatic ring and pyridine structure. This parameter optimization enhances binding affinity to sGC, producing potent effects at lower dosages compared to existing stimulators.
Solution Approach 2:
The invention applies local quality enhancement by introducing electron-withdrawing groups (halogens, cyano, nitro) at specific positions on the aromatic ring system. These localized modifications create regions of increased electron density variation that enhance interaction with sGC active site residues, improving efficacy without increasing overall dosage.
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, increasing cGMP levels and providing therapeutic benefits for conditions like hypertension, angina pectoris, and atherosclerosis without the drawbacks of existing treatments, such as tolerance development and reduced efficacy.
Implementation Method 1
The compounds activate soluble guanylate cyclase and are valuable pharmaceutically active compounds for the therapy and prophylaxis of diseases
Data Source
AI summary
This inventions relates to compounds having the structure Formula I I and pharmaceutically acceptable salts thereof which are soluble guanylate cyclase activators. The compounds are useful for treatment or prevention of cardiovascular diseases, endothelial dysfunction, diastolic dysfunction, atherosclerosis, hypertension, pulmonary hypertension, angina pectoris, thromboses, restenosis, myocardial infarction, strokes, cardiac insufficiency, pulmonary hypertonia, erectile dysfunction, asthma bronchiale, chronic kidney insufficiency, diabetes, or cirrhosis of the liver.