Furopyridine Compounds for Hepatitis C NS5B Inhibition

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Solution Overview

Problem

Current treatments for hepatitis C virus (HCV) infection, particularly those involving HCV-796, face challenges with hepatic toxicity and limited efficacy, necessitating the development of novel compounds with improved mechanism of action, binding affinity, target selectivity, solubility, safety profiles, and bioavailability.

Innovation Solution

Development of novel compounds of formula I, including pharmaceutically acceptable salts and stereoisomers, which demonstrate activity against HCV NS5B, potentially used in combination with interferon and ribavirin to enhance treatment efficacy while minimizing toxicity.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If HCV-796 and similar compounds are used to treat hepatitis C, then viral RNA levels are reduced, but hepatic toxicity occurs and efficacy is limited

Engineering Contradiction:

Improvetreatment efficacyVSAvoidhepatic toxicity

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The patent applies parameter changes by modifying the chemical structure of NS5B inhibitor compounds (formula I) to optimize their pharmacological properties. Specific substitutions at positions R0-R9 are designed to alter binding affinity, selectivity, and metabolic stability, thereby improving efficacy while reducing hepatic toxicity compared to HCV-796

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The patent creates composite pharmaceutical compositions combining compound I with interferon and/or ribavirin. This combination therapy approach leverages multiple mechanisms of action to achieve synergistic antiviral effects, improving overall treatment efficacy while allowing for reduced dosing of individual components to minimize toxicity

Inventive Principle:

Principle #40Composite materials

2Adaptability or versatility

If current standard therapies (interferon and ribavirin) are used, then treatment coverage is broad, but sustained efficacy is achieved in only 40% of patients

Engineering Contradiction:

Improvetreatment coverageVSAvoidsustained efficacy

Core Design Contradiction:

Adaptability or versatilityVSReliability

Solution Approach 1:

The patent merges compound I with existing standard therapies (interferon and/or ribavirin) in combination regimens. This merging of therapeutic agents with different mechanisms of action aims to achieve broader and more reliable efficacy across diverse patient populations, overcoming the limitation of 40% sustained response rates with standard therapy alone

Inventive Principle:

Principle #5Merging (Combining)

3Manufacturing precision

If novel compounds with improved mechanism of action are developed, then binding affinity and target selectivity are enhanced, but compound complexity increases

Engineering Contradiction:

Improvebinding affinityVSAvoidcompound structure complexity

Core Design Contradiction:

Manufacturing precisionVSDevice complexity

Solution Approach 1:

The patent applies local quality by making specific, targeted substitutions at defined positions (R0-R9) on the core pyridine structure. Each substitution is designed to locally optimize interactions with specific residues in the NS5B binding pocket, enhancing binding affinity and selectivity without requiring complete redesign of the entire molecular framework, thus managing complexity

Inventive Principle:

Principle #3Local quality

Data Source

PatentUS9957278B2Furopyridine compounds for the treatment of hepatitis C

Publication Date: 2018.05.01 BRISTOL MYERS SQUIBB CO

AI summary

Compounds of formula I, including their salts, as well as compositions and methods of using the compounds are set forth. The compounds have activity against hepatitis C virus (HCV) and may be useful in treating those infected with HCV.