Alkoxy Pyrazoles as sGC Activators for Portal Hypertension
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Solution Overview
Problem
Current treatments for portal hypertension, a complication of liver cirrhosis, are limited and do not effectively reduce intrahepatic resistance or prevent hepatic fibrosis, with non-selective beta-blockers and nitrates having systemic side effects and inadequate mechanisms for addressing the underlying oxidative stress and endothelial dysfunction.
Innovation Solution
Development of specific heterocyclic compounds that activate soluble guanylate cyclase (sGC), either by binding to the heme-dependent or heme-independent mechanisms, to enhance cGMP production and reduce portal pressure, thereby treating, preventing, or slowing the progression of portal hypertension.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Stress or pressure
If non-selective beta-blockers and nitrates are used to treat portal hypertension, then portal pressure is reduced, but systemic side effects occur and intrahepatic resistance is not effectively reduced
Solution Approach 1:
The patent applies local quality by developing sGC activators that specifically target the liver's endothelial cells and sinusoidal vasculature. The compounds act locally on soluble guanylate cyclase in the hepatic tissue to increase cGMP production and reduce intrahepatic resistance, while minimizing systemic circulation effects. This localized action at the hepatic level addresses portal hypertension without the broad systemic side effects of non-selective beta-blockers and nitrates.
2Stress or pressure
If non-selective beta-blockers and nitrates are used to treat portal hypertension, then portal pressure is reduced, but intrahepatic resistance is not effectively reduced
Solution Approach 1:
The patent employs sGC activators as intermediary compounds that specifically interact with soluble guanylate cyclase in hepatic endothelial cells. These activators serve as a targeted mediator to trigger the NO-cGMP signaling pathway locally within the liver, producing vasodilation and reduced intrahepatic resistance. This intermediary mechanism ensures reliable reduction of intrahepatic resistance by directly activating the downstream cGMP pathway without relying on systemic hemodynamic effects.
3Ease of operation
If conventional treatments are used for portal hypertension, then some symptomatic relief is achieved, but the underlying oxidative stress and endothelial dysfunction are not addressed
Solution Approach 1:
The patent applies preliminary action by using sGC activators to proactively address the underlying oxidative stress and endothelial dysfunction before they progress to decompensated cirrhosis. The compounds preemptively restore NO signaling through sGC activation, reducing oxidative stress markers and improving endothelial function. This preliminary therapeutic intervention targets the root causes of portal hypertension, preventing disease progression rather than merely providing symptomatic relief.
4Reliability
If sGC activators are used to bypass NO signaling impairments, then targeted treatment of portal hypertension is achieved, but compound specificity and selectivity must be optimized
Solution Approach 1:
The patent applies parameter changes by systematically optimizing the chemical structure of sGC activator compounds to achieve the desired balance between potency and selectivity. The invention modifies molecular parameters such as substituent groups on the pyrazole core, halogen atoms, and alkoxy chains to fine-tune the compounds' affinity for sGC versus other targets. This parameter optimization ensures high targeted treatment efficacy while maintaining adequate compound specificity for safe and effective therapy.
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
The sGC activator compounds effectively decrease portal pressure, inhibit fibrosis, and improve liver function by bypassing NO signaling impairments, offering a more targeted approach than existing treatments by reducing intrahepatic resistance and fibrosis in cirrhotic livers.
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)
Implementation Method 2
Under normal conditions, the iron in sGC exists in the ferrous state which is capable of binding to NO and carbon monoxide (CO)
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, for use in the treatment of diseases or disorders that can be alleviated by sGC activation or potentiation, selected from chronic liver diseases, Non-Alcoholic Steatohepatitis (NASH), cirrhosis and portal hypertension.