Soluble Guanylate Cyclase Activators Tolerant to Nitrate Resistance
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Solution Overview
Problem
Current pharmacological stimulation of soluble guanylate cyclase (sGC) for treating cardiovascular diseases and related disorders is limited by the development of tolerance and requires higher dosages, and existing compounds have weak effects on cGMP formation.
Innovation Solution
Development of specific compounds, such as those represented by Formula I, which activate soluble guanylate cyclase, modulating cGMP production to treat cardiovascular diseases and disorders associated with disturbed cGMP balance.
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 is reduced requiring higher dosages
Solution Approach 1:
The patent changes the chemical structure parameters of sGC activators by introducing specific heterocyclic groups (pyrazole, triazole, tetrazole, imidazole, oxadiazole, thiadiazole) and their derivatives as core structures. This structural parameter change creates compounds that activate sGC through a different mechanism than organic nitrates, thereby avoiding tolerance development while maintaining therapeutic effectiveness.
Solution Approach 2:
The patent employs composite molecular structures combining heterocyclic cores with various substituent groups (aryl, heteroaryl, alkyl, halo substituents). These composite structures create novel sGC activators with improved pharmacological properties, including sustained activity without tolerance, addressing the limitation of 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 systematically varying substituents on the heterocyclic core (different aryl, heteroaryl, alkyl, and halo groups). This parameter optimization enhances the compounds' ability to stimulate sGC and increase cGMP formation, directly addressing the weakness of existing stimulators.
Solution Approach 2:
The patent introduces specific local structural features (electron-withdrawing or electron-donating substituents at specific positions on the heterocyclic ring) to enhance local interaction with sGC. This local quality modification improves the efficiency of cGMP formation without requiring increased dosages.
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, thereby providing therapeutic and prophylactic benefits for conditions like hypertension, heart failure, and erectile dysfunction without the limitations of existing treatments.
Implementation Method 1
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. The associated release of the histidine which is bound in the basal state to the iron converts the enzyme into the active conformation.
Data Source
AI summary
The invention relates to compounds having the structure of Formula (I) and pharmaceutically acceptable salts thereof, which are soluble guanylate cyclase activators. The compounds are capable of modulating the body's production of cyclic guanosine monophosphate (“cGMP”) and are generally suitable for the therapy and prophylaxis of diseases which are associated with a disturbed cGMP balance. 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.