sGC Stimulator Compounds for NO–cGMP Pathway Dysfunction
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Solution Overview
Problem
Current therapies for diseases associated with reduced nitric oxide (NO) concentrations or responsiveness to endogenously produced NO lack effectiveness in addressing the underlying NO-sGC pathway dysfunction.
Innovation Solution
Development of novel sGC stimulators, represented by compounds of Formula I and their pharmaceutically acceptable salts, which enhance the enzymatic conversion of GTP to cGMP by synergistically working with NO to stimulate the sGC enzyme.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If current alternative therapies targeting the NO-sGC pathway are used, then some therapeutic effects are achieved, but the underlying NO-sGC pathway dysfunction is not addressed effectively
Solution Approach 1:
The patent introduces sGC stimulators as intermediary compounds that bind to and activate the sGC enzyme, serving as a mediator between NO production and downstream cGMP effects. These stimulators enhance the enzymatic conversion of GTP to cGMP, directly addressing the pathway dysfunction while maintaining therapeutic effectiveness.
Solution Approach 2:
The patent modifies the biochemical parameters of the NO-sGC pathway by introducing compounds that change the enzymatic activity state of sGC. The stimulators alter the enzyme's conformational state to increase its catalytic efficiency, thereby changing the rate of cGMP production and restoring normal pathway function.
2Reliability
If sGC stimulators are developed to enhance enzymatic conversion of GTP to cGMP, then cGMP levels increase and therapeutic benefits are achieved, but new compound development complexity increases
Solution Approach 1:
The patent designs sGC stimulators with multi-functional characteristics that can address multiple disease states through a common mechanism. The stimulators are structurally designed to bind to the heme pocket of sGC and activate it across different physiological contexts, reducing the need for disease-specific compound development.
Solution Approach 2:
The patent employs computational modeling and in silico screening to virtual-screen and prioritize candidate compounds before synthesis. This copying approach allows extensive virtual exploration of chemical space to identify optimal stimulators, reducing the physical complexity of compound development and screening.
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 stimulators increase cGMP levels, modulating downstream effectors and providing therapeutic benefits such as vasodilation, anti-inflammatory effects, and treating a wide range of diseases by improving NO bioavailability and responsiveness.
Implementation Method 1
NO activates its catalytic domain and results in the conversion of guanosine-5′-triphosphate (GTP) into the secondary messenger cGMP
Implementation Method 2
sGC stimulators are heme-dependent agonists of the sGC enzyme that work synergistically with varying amounts of NO to increase its enzymatic conversion of GTP to cGMP
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
The present disclosure relates to stimulators of soluble guanylate cyclase (sGC), pharmaceutically acceptable salts, pharmaceutical formulations comprising them as well as their phosphate ester prodrugs, and their uses alone or in combination with one or more additional agents, for treating various diseases, wherein an increase in the concentration of nitric oxide (NO) and/or an increase in the concentration of cyclic Guanosine Monophosphate (cGMP), or both, or the upregulation of the NO pathway is desirable. The compounds are of Formula I