NO-Independent sGC Stimulators for Pulmonary Hypertension
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Current therapies for conditions related to reduced nitric oxide bioavailability and responsiveness, such as pulmonary hypertension, erectile dysfunction, and cardiovascular diseases, are inadequate, highlighting the need for novel stimulators of soluble guanylate cyclase (sGC) that can increase cyclic Guanosine Monophosphate (cGMP) levels independently of nitric oxide.
Innovation Solution
Development of novel sGC stimulators, specifically compounds represented by certain formulae and their pharmaceutically acceptable salts, which are NO-independent, heme-dependent, and synergistic with NO to stimulate cGMP synthesis, addressing various cardiovascular, sexual, and metabolic disorders.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If current therapies are used for conditions related to reduced nitric oxide bioavailability, then treatment of cardiovascular and sexual disorders is attempted, but therapeutic efficacy is inadequate
Solution Approach 1:
The patent develops novel sGC stimulator compounds with modified chemical structures (Formula I and Formula II) that change the pharmacological parameters of NO-independent sGC stimulation, achieving superior therapeutic efficacy compared to existing therapies for pulmonary hypertension, erectile dysfunction, and cardiovascular diseases
2Adaptability or versatility
If NO-independent sGC stimulators are developed, then cGMP synthesis is stimulated independently of nitric oxide, but dependency on heme moiety is required
Solution Approach 1:
The patent describes NO-independent sGC stimulators that act as intermediary compounds, directly binding to and stimulating soluble guanylate cyclase without requiring nitric oxide as a mediator, thereby achieving NO-independent cGMP synthesis while maintaining heme-dependent mechanism
3Ease of operation
If sGC stimulators are used to promote smooth muscle relaxation, then vasodilation is achieved, but treatment of multiple disease conditions requires broad applicability
Solution Approach 1:
The patent demonstrates that the developed sGC stimulator compounds possess universal therapeutic applications across multiple disease conditions including pulmonary hypertension, erectile dysfunction, cardiovascular diseases, and inflammatory disorders, all through the common mechanism of NO-independent sGC stimulation and cGMP elevation
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 and prevent a wide range of disorders by promoting vasodilation, inhibiting platelet aggregation, and offering anti-hypertensive, anti-inflammatory, and anti-apoptotic effects, improving conditions like pulmonary hypertension, heart failure, atherosclerosis, and erectile dysfunction.
Implementation Method 1
sGC can be activated via both NO-dependent and NO-independent mechanisms. In response to this activation, sGC converts GTP into the secondary messenger cyclic GMP (cGMP).
Implementation Method 2
crucial dependency on the presence of the reduced prosthetic heme moiety for their activity
Implementation Method 3
The increased level of cGMP, in turn, modulates the activity of downstream effectors including protein kinases, phosphodiesterases (PDEs) and ion channels.
Data Source
AI summary
Compounds of Formulae I' and I are described, which are useful as stimulators of sGC, particularly NO-independent, heme-dependent stimulators. These compounds are also useful for treating, preventing or managing various disorders that are herein disclosed.