Dual NEP ECE-1 Inhibitors for Glaucoma Retinal Protection
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Solution Overview
Problem
Current treatments for glaucoma do not effectively mitigate ocular blood flow changes or prevent the death of retinal ganglion cells through apoptosis, which are significant risk factors for the progression of the disease.
Innovation Solution
Development of dual inhibitors of endothelin converting enzyme-1 (ECE-1) and neutral endopeptidase (NEP) or human soluble endopeptidase (hSEP), combined with other pharmaceutical agents, to prevent apoptosis in rodent models similar to those observed in human eye diseases, including glaucoma, by regulating intraocular pressure and blood flow.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Stress or pressure
If current treatments for glaucoma are used to lower intraocular pressure, then intraocular pressure is reduced, but ocular blood flow changes and retinal ganglion cell apoptosis are not effectively mitigated
Solution Approach 1:
The patent combines multiple therapeutic mechanisms into a single compound by designing dual inhibitors that simultaneously target both endothelin converting enzyme-1 (ECE-1) and neutral endopeptidase (NEP). This merging of functions allows the drug to address multiple pathological pathways (intraocular pressure regulation, blood flow maintenance, and apoptosis prevention) through one agent, thereby achieving comprehensive protection against glaucoma progression.
Solution Approach 2:
The dual inhibitor compound performs multiple therapeutic functions: it inhibits ECE-1 to reduce endothelin-1 production (lowering intraocular pressure), inhibits NEP to prevent breakdown of protective peptides like ANP (maintaining ocular blood flow), and thereby provides multifaceted protection against retinal ganglion cell apoptosis. This multi-functionality addresses the limitation of conventional single-target therapies.
2Stress or pressure
If endothelin converting enzyme-1 (ECE-1) is inhibited to reduce endothelin-1 production, then intraocular pressure is lowered, but ocular blood flow regulation and apoptosis prevention are not addressed
Solution Approach 1:
The patent merges ECE-1 inhibition with NEP inhibition in a single dual-specificity compound. By incorporating structural features that allow binding to both enzymes, the invention expands therapeutic coverage from merely pressure reduction to include blood flow regulation and apoptosis prevention, thereby achieving versatile protection against multiple glaucoma pathological processes.
3Reliability
If neutral endopeptidase (NEP) is inhibited to prevent apoptosis and regulate blood flow, then retinal ganglion cell protection is improved, but intraocular pressure regulation is not addressed
Solution Approach 1:
The dual inhibitor design merges NEP inhibition (for apoptosis prevention and blood flow regulation) with ECE-1 inhibition (for intraocular pressure control) in a single compound. This combination ensures that therapeutic intervention addresses the complete spectrum of glaucoma pathology including pressure, perfusion, and cell survival, providing comprehensive disease management.
4Ease of operation
If conventional single-target therapies are used, then treatment simplicity is maintained, but comprehensive protection against multiple pathological processes is not achieved
Solution Approach 1:
The dual inhibitor compound embodies multi-functionality by simultaneously targeting ECE-1 and NEP, thereby addressing multiple pathological mechanisms (intraocular pressure elevation, ocular blood flow reduction, and apoptosis) through a single therapeutic agent. This maintains treatment simplicity while achieving comprehensive disease protection, resolving the contradiction between ease of use and therapeutic effectiveness.
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 dual inhibitors significantly reduce apoptosis in both liver and retinal ganglion cells, demonstrating potential therapeutic value for treating and prophylaxis of various eye diseases, including glaucoma, by effectively managing intraocular pressure and ocular blood flow.
Implementation Method 1
Endothelin converting enzyme-1 (ECE-1), a membrane-bound metalloprotease, catalyses proteolytic activation of Big endothelin-1 to ET-1
Implementation Method 2
Neutral endopeptidase (NEP), a zink metallopeptidase, degrades atrial natriuretic peptide (ANP)
Implementation Method 3
Natriuretic peptide receptor NPrA regulates intracellular cGMP concentration by stimulating particulate guanylyl cyclase (pGC)
Data Source
AI summary
The invention relates to a novel use of benzazepine, benzoxazepine, benzothiazepine-N-acetic acid and phosphono-substituted benzazepinone derivatives having both neutral endopeptidase (NEP) and/or human soluble endopeptidase (hSEP), and endothelin convertase (ECE) inhibitory activity. The compounds of the invention are useful for the preparation of pharmaceutical compositions for prophylaxis and treatment of eye diseases.