Selective MASP-2 Small-Molecule Inhibitors for Complement Control

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Solution Overview

Problem

There is a need for compounds that can selectively inhibit mannan-binding lectin-associated serine protease-2 (MASP-2) to treat MASP-2 complement pathway-associated diseases and disorders, as large molecule biologic inhibitors may not be suitable or efficient for this purpose.

Innovation Solution

Development of synthetic inhibitors of MASP-2, including compounds with Structure (I), which selectively inhibit MASP-2 over thrombin, for use in pharmaceutical compositions to treat MASP-2-associated diseases and disorders.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If large molecule biologic inhibitors are used to target MASP-2, then MASP-2 complement pathway activity can be inhibited, but the compounds may not be suitable or efficient for treatment and have limitations in administration and efficacy

Engineering Contradiction:

Improvetherapeutic efficacyVSAvoidmolecule size complexity

Core Design Contradiction:

ReliabilityVSDevice complexity

Solution Approach 1:

The patent replaces large molecule biologic inhibitors with small molecule synthetic inhibitors that can be administered orally and have favorable pharmacokinetic properties. The small molecule compounds are designed to be metabolically stable and suitable for repeated dosing, effectively replacing the need for complex biologic agents.

Inventive Principle:

Principle #27Cheap short-living objects (Disposable)

Solution Approach 2:

The patent substitutes the biological system (large molecule biologic inhibitors requiring injection and complex distribution) with a chemical system (small molecule compounds with oral bioavailability). This replacement leverages the advantages of small molecules in terms of administration ease, tissue penetration, and metabolic stability.

Inventive Principle:

Principle #28Mechanics substitution (Replace mechanical system)

2Reliability

If MASP-2 is inhibited to treat complement pathway-associated diseases, then therapeutic benefits are achieved, but there is a risk of affecting other protease activities such as thrombin

Engineering Contradiction:

ImproveselectivityVSAvoidoff-target effects

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The patent employs structure-based drug design to create inhibitors with specific molecular features that match the unique active site geometry and chemical environment of MASP-2. The compounds contain functional groups and spatial arrangements that selectively interact with MASP-2 residues while avoiding thrombin binding sites, achieving high selectivity through localized molecular recognition.

Inventive Principle:

Principle #3Local quality

Solution Approach 2:

The patent uses computational modeling and structure-activity relationship studies as intermediaries to identify and optimize selective inhibition. By analyzing the structural differences between MASP-2 and thrombin, the invention designs compounds that act as selective mediators targeting only MASP-2 without cross-reacting with thrombin or other proteases.

Inventive Principle:

Principle #24Intermediary (Mediator)

Data Source

PatentUS12486278B2MASP-2 inhibitors and methods of use

Publication Date: 2025.12.02 OMEROS CORP

AI summary

The present disclosure provides, inter alia, compounds with MASP-2 inhibitory activity, compositions of such compounds, and methods of making and using such compounds.