sGC Activators for Glaucoma via Oxidized Enzyme Targeting
Solution Overview
Problem
Current glaucoma treatments are inadequate for patients with normotensive or low-tension glaucoma, as they often do not respond well to existing therapies, and there is a need for effective methods to lower intraocular pressure (IOP) without significant side effects, especially in cases where oxidative stress compromises the function of soluble guanylate cyclase (sGC) in the trabecular meshwork.
Innovation Solution
Development of selective sGC activators that can activate the oxidized form of sGC in the trabecular meshwork, independent of nitric oxide, to modulate intraocular pressure and treat glaucoma, including primary open-angle glaucoma, by formulating these activators for topical delivery to the eye.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Stress or pressure
If conventional therapeutic agents are used to reduce IOP, then IOP lowering effect is achieved, but side effects occur which may render them undesirable
Solution Approach 1:
The patent introduces soluble guanylate cyclase (sGC) as an intermediary target in the IOP lowering pathway. Instead of directly affecting aqueous humor production or outflow, the compounds activate sGC which then modulates IOP through downstream signaling pathways (cGMP production), providing a more indirect and selective mechanism that reduces side effects
Solution Approach 2:
The patent changes the therapeutic parameter from direct IOP manipulation to sGC activation. The compounds modify the biochemical state of sGC (activating it), which then naturally regulates IOP through physiological pathways, thereby achieving IOP control with a different mechanism that avoids conventional side effects
2Stress or pressure
If existing glaucoma therapies are applied, then IOP is lowered, but patients with normotensive or low-tension glaucoma do not respond well
Solution Approach 1:
The patent addresses treatment resistance by changing the therapeutic parameter to sGC activation, which operates through a different physiological pathway than conventional agents. This alternative mechanism bypasses the resistance encountered with traditional IOP-lowering therapies, making it effective even in normotensive or low-tension glaucoma cases where conventional treatments fail
3Power
If sGC stimulators are used, then cGMP production is enhanced, but they become inactive once sGC is oxidized under oxidative stress
Solution Approach 1:
The patent converts the harmful effect of oxidative stress (sGC oxidation leading to unresponsiveness) into a beneficial target. The compounds are specifically designed to activate the oxidized form of sGC, thereby converting the pathological state (oxidized, unresponsive sGC) into a treatable target that restores cGMP production even under oxidative stress conditions
Solution Approach 2:
Instead of trying to protect sGC from oxidation or restore reduced sGC function, the patent inverts the approach by directly targeting and activating the oxidized form of sGC. This inverted strategy accepts the oxidized state as the target rather than trying to prevent or reverse it, thereby restoring functionality in a fundamentally different manner
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 targeting the oxidized form of sGC in the trabecular meshwork, offering a novel therapeutic approach that complements existing treatments and addresses oxidative stress-induced complications.
Implementation Method 1
soluble guanylate cyclase (sGC) is a receptor enzyme for the second messenger, nitric oxide (NO)... 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.