Small Molecule MASP-2 Inhibitors for Complement Therapy

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Solution Overview

Problem

There is a need for compounds that can effectively inhibit MASP-2 associated diseases and disorders, particularly those not suitably treated with large molecule biologic inhibitors.

Innovation Solution

A compound with Formula (I) or its stereoisomer, tautomer, or pharmaceutically acceptable salt, which inhibits MASP-2 by binding to specific sites on the enzyme, thereby reducing its activity and associated disease pathogenesis.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If large molecule biologic inhibitors are used to treat MASP-2-associated diseases, then complement activation can be inhibited, but the treatment is not suitable for all disease states and has limitations in certain conditions

Engineering Contradiction:

Improvetreatment effectivenessVSAvoidapplicability to different disease states

Core Design Contradiction:

ReliabilityVSAdaptability or versatility

Solution Approach 1:

The patent changes the molecular parameter from large molecule biologics to small molecule compounds, enabling the inhibitor to cross biological membranes and reach targets in conditions where large molecules cannot penetrate, thus expanding adaptability to different disease states while maintaining treatment effectiveness

Inventive Principle:

Principle #35Parameter changes

2Adaptability or versatility

If small molecule compounds are designed to inhibit MASP-2, then they can potentially treat diseases not suitable for large molecule inhibitors, but the design and synthesis complexity increases

Engineering Contradiction:

Improveapplicability to different disease statesVSAvoidcompound synthesis

Core Design Contradiction:

Adaptability or versatilityVSEase of manufacture

Solution Approach 1:

The patent segments the MASP-2 enzyme into distinct functional domains (lectin-like domain, serine protease domain, etc.) and designs inhibitors that target specific regions, simplifying the overall design process by focusing on key interaction sites rather than the entire complex enzyme structure

Inventive Principle:

Principle #1Segmentation

Solution Approach 2:

The patent uses structure-activity relationship (SAR) studies and computational modeling as intermediaries to guide the optimization of small molecule compounds, bridging the gap between initial compound design and final optimized inhibitor with reduced synthesis complexity

Inventive Principle:

Principle #24Intermediary (Mediator)

Data Source

PatentUS20250122225A1MASP-2 inhibitors and methods of use

Publication Date: 2025.04.17 OMEROS CORP

AI summary

The disclosure provides synthetic compositions useful as inhibitors of mannan-binding lectin-associated serine protease-2 (MASP-2), including inhibitors that selectively inhibit MASP-2 over thrombin, as well as methods for the manufacture and use thereof.