2'-Spiro-nucleosides for Hepatitis C Therapy

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Solution Overview

Problem

Current treatments for hepatitis C virus (HCV) and dengue virus infections are limited, with no effective vaccines or specific therapies available, and existing antiviral agents face challenges such as poor physicochemical and pharmacokinetic properties, leading to limited efficacy and potential for resistant strains.

Innovation Solution

Development of 2'-spiro-nucleosides and their derivatives that target the NS5B polymerase of HCV and other viral proteins, potentially inhibiting viral replication by acting as chain terminators or competitive inhibitors, and improving pharmacokinetic properties through stable phosphate prodrugs.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If current treatments with interferon-alpha and ribavirin are used, then immunotherapy is provided, but clinical benefit is limited and treatment duration is prolonged

Engineering Contradiction:

Improveclinical benefitVSAvoidtreatment duration

Core Design Contradiction:

ReliabilityVSLoss of time

Solution Approach 1:

The patent modifies the nucleoside structure by introducing a 2'-spiro-oxetane group and varying substituents at the 5-position, which changes the physicochemical parameters of the molecule to improve antiviral activity and pharmacokinetic properties, thereby enhancing clinical benefit and potentially reducing treatment duration

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The invention combines the nucleoside core structure with specific substituent groups (halogens, alkyl groups, cycloalkyl groups) to create composite molecular structures that exhibit synergistic effects, improving both efficacy and pharmacokinetic profile compared to conventional nucleosides

Inventive Principle:

Principle #40Composite materials

2Reliability

If existing antiviral agents are used, then viral replication is inhibited, but physicochemical and pharmacokinetic properties are poor

Engineering Contradiction:

Improveviral replication inhibitionVSAvoidphysicochemical and pharmacokinetic properties

Core Design Contradiction:

ReliabilityVSEase of manufacture

Solution Approach 1:

The patent introduces specific functional groups at particular positions (5-position substituents, 2'-spiro-oxetane group) to locally modify the molecule's properties, enhancing solubility, metabolic stability, and cellular uptake without compromising the core antiviral mechanism against NS5B polymerase

Inventive Principle:

Principle #3Local quality

Solution Approach 2:

The 2'-spiro-oxetane group acts as an intermediary structure that improves the pharmacokinetic properties of the nucleoside by enhancing cellular penetration and metabolic stability, while the variable substituents at the 5-position serve as intermediaries to optimize binding affinity to the viral polymerase

Inventive Principle:

Principle #24Intermediary (Mediator)

3Reliability

If conventional nucleoside analogs are used, then antiviral activity is achieved, but resistance development occurs

Engineering Contradiction:

Improveantiviral activityVSAvoidresistance potential

Core Design Contradiction:

ReliabilityVSAdaptability or versatility

Solution Approach 1:

The patent designs nucleoside analogs with a core 2'-spiro-oxetane structure that can accommodate multiple different substituents at the 5-position, creating a series of compounds with diverse structures but similar mechanism of action, which may reduce resistance development by targeting multiple interaction points on the viral polymerase

Inventive Principle:

Principle #6Universality (Multi-functionality)

Data Source

PatentEP3042910B12'-spiro-nucleosides for use in the therapy of hepatitis c

Publication Date: 2019.01.09 GILEAD PHARMASSET LLC

AI summary

Disclosed herein are 2'-spiro-nucleosides of formula I and derivatives thereof useful for treating a subject infected by hepatitis C virus or dengue virus, wherein B is selected from among B2 and B3 represented by the following structures: