Indane Derivatives as Soluble Guanylate Cyclase Activators for Glaucoma
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Solution Overview
Problem
Current glaucoma treatments often fail to achieve desired intraocular pressure (IOP) reduction, especially in normotensive or low-tension glaucoma patients, due to oxidative stress affecting the trabecular meshwork and rendering existing therapies ineffective.
Innovation Solution
Development of selective soluble guanylate cyclase (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.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional glaucoma therapies are used to reduce intraocular pressure, then IOP reduction is achieved in some patients, but they fail to achieve desired IOP reduction in normotensive or low-tension glaucoma patients due to oxidative stress affecting the trabecular meshwork
Solution Approach 1:
The patent changes the mechanism of action from NO-dependent sGC stimulation to NO-independent sGC activation. The compounds directly activate sGC by binding to the heme group and stabilizing the ferrous state, bypassing the need for nitric oxide. This parameter change in the activation mechanism allows the therapy to work effectively in normotensive and low-tension glaucoma patients where conventional NO-dependent therapies fail due to oxidative stress.
2Reliability
If sGC stimulators are used to activate sGC, then cGMP production is increased, but they become inactive once sGC is oxidized by prolonged oxidative stress
Solution Approach 1:
The patent converts the harmful effect of oxidative stress (which oxidizes the heme group and inactivates sGC stimulators) into a beneficial target. The sGC activators are specifically designed to bind to and activate the oxidized form of sGC, transforming the pathological oxidation state into a therapeutic opportunity. This allows continuous therapeutic action even in the presence of prolonged oxidative stress that would inactivate conventional sGC stimulators.
3Reliability
If existing glaucoma therapies are administered topically or orally, then IOP reduction is achieved through decreasing aqueous humor production or increasing outflow facility, but many agents have associated side effects that render them undesirable
Solution Approach 1:
The patent introduces sGC activators as a new intermediary mechanism in the IOP control pathway. Instead of directly affecting aqueous humor production or outflow facility, the compounds act through the cGMP signaling pathway by activating sGC. This intermediary approach provides a more selective and targeted mechanism that achieves IOP reduction with fewer off-target side effects compared to conventional therapies.
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 normal-tension glaucoma and ocular hypertension, providing a novel therapeutic approach that complements existing treatments by targeting oxidative stress-induced enzyme inactivation.
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).
Implementation Method 2
Under aforementioned pathologic conditions, prolonged oxidative stress can cause the oxidation of the heme group of sGC (from ferrous to ferric state) which is incapable of being activated by NO and can contribute to exacerbation of disease processes.
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.