Alkoxy Pyrazole sGC Activators for Oxidized Heme Iron
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Solution Overview
Problem
Current treatments for various diseases mediated by decreased soluble guanylate cyclase activity, such as cardiovascular 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 soluble guanylate cyclase, providing therapeutic benefits by bypassing functional impediments in the NO pathway and targeting diseased enzyme forms.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional treatments are used for diseases mediated by decreased soluble guanylate cyclase activity, then treatment coverage is provided, but efficacy and specificity are limited particularly when heme iron oxidation impairs NO signaling
Solution Approach 1:
The patent applies parameter changes by developing compounds that specifically target and bind to the oxidized heme iron form of soluble guanylate cyclase, changing the therapeutic approach from general sGC activation to specific targeting of the oxidized, non-functional form. This specificity resolves the contradiction by maintaining high treatment efficacy while adapting to the specific pathological condition of heme iron oxidation.
Solution Approach 2:
The patent introduces sGC activator compounds as intermediaries that bridge the gap between NO signaling impairment and therapeutic effect. These compounds act as mediators that can restore sGC function even when NO signaling is impaired by heme iron oxidation, thereby improving treatment efficacy without requiring specific adaptation to each underlying cause.
2Reliability
If sGC activators are developed to bypass functional impediments in the NO pathway, then therapeutic benefit is achieved, but compound solubility and pharmacokinetic properties may be compromised
Solution Approach 1:
The patent applies parameter changes by systematically modifying the chemical structure of sGC activator compounds, specifically incorporating alkoxy groups at the 5-position of the pyrazole ring. This structural modification changes the solubility parameters of the compounds while maintaining their ability to activate sGC, thereby resolving the contradiction between therapeutic benefit and manufacturability.
Solution Approach 2:
The patent applies local quality by making specific localized modifications to the molecular structure of sGC activators - adding alkoxy groups at particular positions (5-position of pyrazole ring) while leaving other parts of the molecule intact. This localized modification improves solubility without compromising the core therapeutic activity, resolving the contradiction between efficacy and manufacturability.
3Object-affected harmful factors
If heme iron oxidation occurs under oxidative stress conditions, then NO signaling is impaired, but disease processes are sustained
Solution Approach 1:
The patent applies the blessing in disguise principle by developing sGC activator compounds that specifically target and bind to oxidized heme iron forms of sGC. Instead of trying to prevent heme iron oxidation or restore NO signaling through conventional means, the invention converts the harmful oxidized form into a beneficial therapeutic target, allowing activation of sGC even in the presence of oxidative stress and heme iron oxidation.
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 alleviate a range of diseases by enhancing cGMP production, reducing inflammation, improving renal and cardiovascular functions, and addressing conditions like hypertension, fibrosis, and erectile dysfunction.
Implementation Method 1
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 and R7 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.