Macrocyclic Compounds Inhibiting HCV NS3 Protease

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Solution Overview

Problem

Current treatments for Hepatitis C virus (HCV) infection are limited in clinical benefit, and there is a need for more effective therapeutic agents to combat chronic HCV infection, as existing therapies like immunotherapy with interferon-α and ribavirin have limitations, and no vaccine is established.

Innovation Solution

Development of macrocyclic compounds that inhibit the HCV NS3 protease, specifically compounds of formula (I) and their pharmaceutically acceptable salts, which are designed to target the NS3 protease to prevent or treat HCV infection.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If immunotherapy with interferon-α and ribavirin is used to treat HCV infection, then treatment coverage is provided, but clinical benefit is limited

Engineering Contradiction:

Improveclinical benefitVSAvoidtreatment effectiveness

Core Design Contradiction:

ReliabilityVSAdaptability or versatility

Solution Approach 1:

The patent changes the therapeutic parameter from immunotherapy (interferon-α and ribavirin) to direct antiviral protease inhibition using macrocyclic compounds. This parameter change addresses the limited clinical benefit by targeting the viral NS3 protease directly, thereby improving treatment effectiveness while maintaining reliable administration protocols.

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The patent substitutes the immunotherapy mechanism (relying on host immune response) with a direct biochemical inhibition mechanism. The macrocyclic compounds directly inhibit the NS3 protease enzymatic activity, replacing the indirect immunological approach with a more precise molecular intervention that overcomes the limitations of interferon-based therapy.

Inventive Principle:

Principle #28Mechanics substitution (Replace mechanical system)

2Adaptability or versatility

If no vaccine is established for HCV, then prevention options are limited, but this creates urgent need for improved therapeutic agents

Engineering Contradiction:

Improveprevention optionsVSAvoidtherapeutic effectiveness

Core Design Contradiction:

Adaptability or versatilityVSReliability

Solution Approach 1:

The patent develops prophylactic therapeutic agents that can be administered to prevent HCV infection or treat early-stage infection before chronic disease develops. The macrocyclic compounds act in advance to inhibit viral replication, providing a preliminary protective measure that compensates for the lack of vaccination options.

Inventive Principle:

Principle #10Preliminary action

3Reliability

If macrocyclic compounds are designed to inhibit HCV NS3 protease, then antiviral activity is achieved, but compound complexity increases

Engineering Contradiction:

Improveantiviral activityVSAvoidcompound structure

Core Design Contradiction:

ReliabilityVSDevice complexity

Solution Approach 1:

The patent segments the NS3 protease inhibitor into distinct functional modules within the macrocyclic structure: a P1-P4 peptide region for substrate recognition, a macrocyclic core for structural stability and binding, and substitutable R groups for optimizing specificity. This segmentation allows complex antiviral activity to be achieved through modular design, making the compound development more systematic and manageable.

Inventive Principle:

Principle #1Segmentation

Data Source

PatentEP2027144B1Macrocyclic compounds as antiviral agents

Publication Date: 2015.04.29 MSD ITALIA SRL

AI summary

The present invention relates to macrocyclic compounds of formula (I): wherein W, n, R1, Ra, Rb, R3, R4, M, Z, ring A and ring B are defined herein, and pharmaceutically acceptable salts thereof, pharmaceutical compositions comprising them, and their use for the treatment or prevention of infection by hepatitis C virus.