Selective Plasma Kallikrein Inhibitors for Vascular Permeability Control
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Solution Overview
Problem
Current treatments for conditions associated with plasma kallikrein activity, such as hereditary angioedema and diabetic macular edema, are limited in their effectiveness and specificity, necessitating the development of more potent and versatile inhibitors.
Innovation Solution
Development of compounds of Formula I, which are plasma kallikrein inhibitors, capable of treating a range of disorders including hereditary angioedema, diabetic macular edema, and diabetic retinopathy, either alone or in combination with other therapeutic agents.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If existing plasma kallikrein inhibitors are used, then treatment is available for hereditary angioedema and diabetic macular edema, but the treatments are limited in effectiveness and specificity
Solution Approach 1:
The patent employs parameter changes by modifying the chemical structure of plasma kallikrein inhibitors through varying substituents R1-R6, ring structures, and molecular configurations to achieve both high effectiveness and specificity. The compounds of Formula I represent a series of structurally diverse inhibitors with optimized binding affinity and selectivity for plasma kallikrein, resolving the contradiction between broad effectiveness and specific targeting.
Solution Approach 2:
The invention applies local quality by designing specific regions within the inhibitor molecules (such as the heteroaryl ring at position Y, substituted phenyl groups, and specific amino acid residues) that interact with particular pockets or residues in the plasma kallikrein active site. This localized optimization of molecular interactions enhances both potency and specificity simultaneously.
2Device complexity
If a single inhibitor compound is used, then the treatment mechanism is simple, but the therapeutic range is limited
Solution Approach 1:
The patent achieves universality by creating a series of compounds (Formula I) that can treat multiple conditions including hereditary angioedema, diabetic macular edema, diabetic retinopathy, and other plasma kallikrein-associated disorders. The core molecular scaffold maintains plasma kallikrein inhibition across different disease contexts, while substituent variations allow optimization for specific indications, enabling one inhibitor class to serve multiple therapeutic purposes.
Data Source
AI summary
The present invention provides a compound of Formula Iand pharmaceutical compositions comprising one or more said compounds, and methods for using said compounds for treating or preventing one or more disease states that could benefit from inhibition of plasma kallikrein, including hereditary angioedema, uveitis, posterior uveitis, wet age related macular edema, diabetic macular edema, diabetic retinopathy and retinal vein occlusion. The compounds are selective inhibitors of plasma kallikrein.