Macrocyclic HCV Entry Inhibitors for Enhanced Efficacy

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Solution Overview

Problem

Current treatments for hepatitis C virus (HCV) infection are limited by low efficacy and severe side effects, with existing therapies only achieving a 50% sustained virologic response for genotype 1 HCV and lacking targeted antiviral options.

Innovation Solution

Development of novel compounds of Formula I, including pharmaceutically acceptable salts, that demonstrate activity against HCV NS5B, potentially offering improved mechanisms of action, binding efficacy, target selectivity, solubility, safety profiles, and bioavailability.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If current treatments (pegylated alpha-interferon and ribavirin) are used, then HCV infection can be treated, but efficacy is limited to 50% sustained virologic response and severe side effects occur

Engineering Contradiction:

Improvesustained virologic responseVSAvoidside effects

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The patent changes the molecular parameters of the antiviral agent by synthesizing novel macrocyclic compounds with specific molecular weights, functional groups, and structural configurations (Formula I compounds). These parameter changes enable the new compounds to achieve higher efficacy (beyond 50% sustained virologic response) while reducing harmful side effects compared to conventional interferon and ribavirin treatments

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The invention creates composite molecular structures by combining multiple functional groups and structural motifs within the macrocyclic framework (Formula I). These composite molecular designs integrate various pharmacological activities to achieve both high efficacy against HCV and reduced toxicity, resolving the contradiction between treatment effectiveness and safety

Inventive Principle:

Principle #40Composite materials

2Reliability

If existing antiviral therapies are used, then HCV treatment is provided, but target selectivity and mechanism of action are non-specific

Engineering Contradiction:

Improvetreatment effectivenessVSAvoidtarget selectivity

Core Design Contradiction:

ReliabilityVSAdaptability or versatility

Solution Approach 1:

The patent applies local quality by designing macrocyclic compounds with specific functional groups and structural features (Formula I) that are tailored to interact with particular HCV targets such as NS5B polymerase. This localized molecular design provides high target selectivity and specific mechanism of action, improving treatment effectiveness through targeted antiviral activity rather than non-specific therapy

Inventive Principle:

Principle #3Local quality

3Reliability

If conventional HCV treatments are administered, then viral infection is addressed, but bioavailability and solubility are insufficient

Engineering Contradiction:

Improvetherapeutic efficacyVSAvoidbioavailability

Core Design Contradiction:

ReliabilityVSEase of manufacture

Solution Approach 1:

The invention modifies key parameters of the antiviral compound including molecular weight, functional group composition, and structural configuration of the macrocyclic compounds (Formula I). These parameter optimizations enhance bioavailability and solubility properties, enabling better absorption, distribution, and metabolic characteristics that improve therapeutic efficacy

Inventive Principle:

Principle #35Parameter changes

Data Source

PatentUS9868743B2Macrocyclic molecules as HCV entry inhibitors

Publication Date: 2018.01.16 BRISTOL MYERS SQUIBB CO

AI summary

Compounds of Formula I, including pharmaceutically acceptable salts thereof, are set forth, in addition to compositions and methods of using these compounds. The compounds have activity against hepatitis C virus (HCV) and may be useful in treating those infected with HCV.