Soluble Guanylate Cyclase Activators for Glaucoma
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Solution Overview
Problem
Current glaucoma therapies often fail to achieve desired intraocular pressure (IOP) reduction, especially in normotensive or low-tension glaucoma patients, and are associated with significant side effects, while oxidative stress compromises the function of soluble guanylate cyclase (sGC) in the trabecular meshwork, leading to unresponsive nitric oxide signaling.
Innovation Solution
Development of selective sGC activators that can activate the oxidized form of sGC, even in the absence of nitric oxide, to modulate intraocular pressure by targeting the trabecular meshwork and Schlemm's canal tissue, thereby providing a novel therapeutic approach for glaucoma treatment.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional IOP-lowering agents are administered, then intraocular pressure is reduced, but side effects increase and therapeutic effectiveness decreases in normotensive glaucoma patients
Solution Approach 1:
The patent applies local quality by designing sGC activators that selectively target oxidized sGC in diseased trabecular meshwork tissue while sparing healthy tissue. The compounds exhibit differential activity based on the oxidative state of sGC, providing localized therapeutic action at the site of pathology without systemic side effects
Solution Approach 2:
The patent utilizes parameter changes by developing compounds that respond to the oxidative state parameter of sGC. The sGC activators are designed to specifically activate the oxidized form of the enzyme, converting the pathological parameter (oxidation) into a therapeutic opportunity rather than treating only the normal state
2Reliability
If sGC stimulators are used, then cGMP production is enhanced under physiological conditions, but they become inactive when sGC is oxidized
Solution Approach 1:
The patent applies inversion by developing sGC activators that work in opposition to conventional stimulators. While stimulators require reduced heme and fail under oxidation, the activators are designed to specifically bind and activate oxidized sGC, inverting the conventional mechanism to address the pathological state directly
Solution Approach 2:
The patent converts the harmful effect of oxidative stress into a beneficial therapeutic opportunity. By designing activators that specifically recognize and activate the oxidized form of sGC, the patent transforms the pathological modification (oxidation) into a target for selective therapeutic action, benefiting from the very change that causes disease
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 activators effectively lower and control IOP in glaucoma patients, including those with primary open-angle glaucoma, by selectively activating the enzyme in diseased tissues, potentially offering a more effective and side-effect-reduced treatment option compared to existing therapies.
Implementation Method 1
soluble guanylate cyclase (sGC) is a receptor enzyme for the second messenger, nitric oxide (NO) in several cell types including muscle, epithelial, neuronal, and endothelial cells. Under physiological conditions, NO binds to the prosthetic heme of sGC which activates the enzyme to catalyze the conversion of guanosine-5'-triphosphate (GTP) to cyclic guanosine monophosphate (cGMP).
Data Source
AI summary
The present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof; a method for manufacturing the compounds of the invention, and its therapeutic uses. The present invention further provides a combination of pharmacologically active agents and a pharmaceutical composition.