Soluble Guanylate Cyclase Activators for Oxidized Enzyme Treatment
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Solution Overview
Problem
Current treatments for various diseases mediated by decreased soluble guanylate cyclase (sGC) activity, such as cardiovascular, renal, and inflammatory disorders, are limited in efficacy and specificity, particularly in conditions where heme iron oxidation impairs NO signaling.
Innovation Solution
Development of novel heterocyclic compounds that activate or potentiate sGC, bypassing the functional impediments caused by heme iron oxidation, thereby enhancing cGMP production and offering therapeutic benefits across multiple disease pathways.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional sGC treatments are used, then some disease symptoms may be alleviated, but efficacy and specificity are limited particularly in conditions where heme iron oxidation impairs NO signaling
Solution Approach 1:
The patent introduces sGC activators as intermediary compounds that bind to and activate the soluble guanylate cyclase enzyme independently of NO signaling. These activators serve as a mediator that bypasses the blocked NO-cGMP pathway, directly stimulating cGMP production even when heme iron is oxidized and cannot bind NO effectively.
Solution Approach 2:
The invention changes the activation parameter of sGC from NO-dependent (requiring ferrous heme iron) to NO-independent (direct activator binding). This parameter change allows the enzyme to be activated under oxidative stress conditions where the traditional NO signaling pathway is compromised, thereby improving therapeutic specificity for these conditions.
2Reliability
If heme iron is oxidized to ferric state, then sGC cannot be activated by NO or CO, but this oxidation occurs in various diseases
Solution Approach 1:
The patent converts the harmful effect of heme iron oxidation (which blocks NO binding) into a beneficial selective activation mechanism. By using sGC activators that bind to the enzyme regardless of heme iron oxidation state, the treatment specifically targets and activates the oxidized, non-functional form of sGC, thereby converting the harmful oxidation state into a target for therapeutic intervention.
3Productivity
If sGC activators are used to bypass NO signaling impediments, then cGMP production is enhanced, but the mechanism is complex
Solution Approach 1:
The invention extracts the essential function of sGC activation from the complex NO-signaling pathway. Instead of relying on the multi-step NO synthesis, diffusion, and heme binding process, the sGC activators directly bind to and activate the enzyme, extracting the critical cGMP production function from the compromised upstream signaling components.
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 treat a wide range of diseases by enhancing sGC activity, including cardiovascular diseases, renal disorders, diabetes, fibrotic conditions, and inflammatory disorders, by targeting the non-functional form of sGC and improving NO signaling pathways.
Implementation Method 1
Under normal conditions, the iron in sGC exists in the ferrous state which is capable of binding to NO and carbon monoxide (CO).
Implementation Method 2
under conditions of oxidative stress which can occur in various diseases, published reports indicate that the heme iron becomes oxidized to the ferric state which is incapable of being activated by NO or CO.
Implementation Method 3
NO binding to the heme of sGC activates the enzyme to catalyze the conversion of guanosine-5'-triphosphate (GTP) to cyclic guanosine monophosphate (cGMP).
Data Source
AI summary
The present invention relates to compounds of formula (I): and pharmaceutically acceptable salts thereof, wherein R1, R2. R3, R4, R5, R6, A and B are as defined herein. The invention also relates to pharmaceutical compositions comprising these compounds, methods of using these compounds in the treatment of various diseases and disorders, processes for preparing these compounds and intermediates useful in these processes.