MASP-2 Serine Protease Inhibitors That Spare Classical Complement

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Solution Overview

Problem

There is a need for small molecule compounds that can selectively inhibit mannan-binding lectin-associated serine protease-2 (MASP-2) to treat MASP-2 complement pathway-associated diseases and disorders without interfering with the antibody-dependent classical complement activation pathway, which is critical for the acquired immune response.

Innovation Solution

Development of small molecule inhibitors that interact with the MASP-2 serine protease domain through specific intermolecular interactions, including hydrogen bonds, ionic or electrostatic interactions, π-π interactions, and van der Waals contacts, to selectively inhibit MASP-2 while sparing thrombin.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If small molecule inhibitors are designed to inhibit MASP-2, then lectin pathway complement activity is blocked, but there is a risk of interfering with the classical complement activation pathway

Engineering Contradiction:

Improveselectivity of MASP-2 inhibitionVSAvoidinterference with classical complement pathway

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The patent applies local quality by designing inhibitors that specifically target the MASP-2 serine protease domain with distinct binding characteristics. The inhibitors are engineered to interact with specific amino acid residues (such as Asp627, Arg630, Ser633, and Glu662) that are unique to or more accessible in MASP-2 compared to other serine proteases like thrombin or factor XIIa. This localized targeting ensures selective inhibition of the lectin pathway while preserving classical pathway function.

Inventive Principle:

Principle #3Local quality

Solution Approach 2:

The patent employs parameter changes by modifying molecular structure parameters of the inhibitors to optimize selectivity. Specific structural features are incorporated, including hydrogen bond donors and acceptors positioned to interact with MASP-2's active site residues, ionic interactions with negatively charged residues, and hydrophobic interactions with specific pockets. These parameter optimizations ensure the inhibitors bind MASP-2 with high affinity while maintaining low affinity for other proteases, thus achieving selective lectin pathway inhibition.

Inventive Principle:

Principle #35Parameter changes

2Reliability

If fully human monoclonal antibodies are used to target MASP-2, then lectin pathway activity is blocked, but the complexity of administration and manufacturing increases

Engineering Contradiction:

Improveefficacy of MASP-2 inhibitionVSAvoidcomplexity of antibody therapy

Core Design Contradiction:

ReliabilityVSDevice complexity

Solution Approach 1:

The patent applies mechanics substitution by replacing the large molecule monoclonal antibody approach with small molecule chemical compounds. This substitution transitions from a biological macromolecule-based therapy to a small molecule-based therapy, thereby reducing manufacturing complexity, improving oral bioavailability potential, and simplifying administration while maintaining MASP-2 inhibition efficacy. The small molecules achieve similar therapeutic goals through chemical binding rather than immunological recognition.

Inventive Principle:

Principle #28Mechanics substitution (Replace mechanical system)

Solution Approach 2:

The patent employs this principle by developing small molecule inhibitors that can be synthesized through chemical processes rather than requiring complex biologic manufacturing. Small molecules generally have simpler, more scalable production processes compared to monoclonal antibodies, reducing manufacturing costs and complexity. The inhibitors can be produced through established chemical synthesis methods, making them more accessible and easier to manufacture at scale.

Inventive Principle:

Principle #27Cheap short-living objects (Disposable)

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 small molecule inhibitors effectively block the lectin pathway complement activity, providing therapeutic benefits for MASP-2-associated diseases and disorders without affecting the classical complement activation pathway.

Implementation Method 1

interact with the MASP-2 serine protease domain through specific intermolecular interactions, including hydrogen bonds

Methodology Applied

Scientific EffectHydrogen bond:

Implementation Method 2

interact with the MASP-2 serine protease domain through specific intermolecular interactions, including hydrogen bonds, ionic or electrostatic interactions

Methodology Applied

Scientific EffectIonic interaction:

Implementation Method 3

interact with the MASP-2 serine protease domain through specific intermolecular interactions, including hydrogen bonds, ionic or electrostatic interactions, π-π interactions

Methodology Applied

Scientific Effectπ-π interaction:

Implementation Method 4

interact with the MASP-2 serine protease domain through specific intermolecular interactions, including hydrogen bonds, ionic or electrostatic interactions, π-π interactions, and van der Waals contacts

Methodology Applied

Scientific Effectvan der Waals force: Van der Waals Force

Data Source

PatentUS20250368604A1MASP-2 inhibitors and methods of use

Publication Date: 2025.12.04 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.