Spirocyclic HBV Inhibitors With Improved Bioavailability

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Solution Overview

Problem

Current HBV inhibitors face challenges such as toxicity, mutagenicity, lack of selectivity, poor efficacy, poor bioavailability, low solubility, and off-target activity, with no approved drugs in any structural class effectively addressing these issues.

Innovation Solution

Development of small molecule drugs with a tricyclic core structure comprising a pyrrole ring and amide or oxalamide substituent, exhibiting improved pharmacokinetic properties, good kinetic solubility, stability in hepatocytes, and low in vivo clearance, designed for hepatoselective distribution.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If current HBV inhibitors are used, then HBV inhibition is achieved, but toxicity and mutagenicity occur

Engineering Contradiction:

ImproveHBV inhibitionVSAvoidtoxicity

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The patent applies parameter changes by developing novel chemical structures with specific molecular characteristics (tricyclic core with pyrrole ring, amide or oxalamide substituent) that fundamentally alter the pharmacokinetic parameters including solubility, stability in hepatocytes, and in vivo clearance, thereby achieving potent HBV inhibition with improved safety profiles and reduced toxicity

Inventive Principle:

Principle #35Parameter changes

2Reliability

If current HBV inhibitors are used, then HBV inhibition is achieved, but poor bioavailability and low solubility occur

Engineering Contradiction:

ImproveHBV inhibitionVSAvoidbioavailability

Core Design Contradiction:

ReliabilityVSQuantity of substance

Solution Approach 1:

The invention changes the physical-chemical parameters of the inhibitor molecules by introducing specific structural features (tricyclic core, pyrrole ring, amide/oxalamide substituents) that improve kinetic solubility and bioavailability while maintaining potent HBV inhibition activity

Inventive Principle:

Principle #35Parameter changes

3Reliability

If current HBV inhibitors are used, then HBV inhibition is achieved, but lack of selectivity and off-target activity occur

Engineering Contradiction:

ImproveHBV inhibitionVSAvoidselectivity

Core Design Contradiction:

ReliabilityVSAdaptability or versatility

Solution Approach 1:

The patent applies local quality by designing molecules with specific localized functional groups (amide or oxalamide substituent on tricyclic core) that provide targeted interaction with HBV targets while minimizing off-target effects, thereby achieving improved selectivity for HBV inhibition

Inventive Principle:

Principle #3Local quality

Data Source

PatentUS12404284B2Spirocyclic inhibitors of hepatitis B virus

Publication Date: 2025.09.02 INSTITUTO NAZIONALE DI GENETICA MOLECOLARE (INGM)

AI summary

The present invention relates to compounds that are inhibitors of hepatitis B virus (HBV). Compounds of this invention are useful alone or in combination with other agents for treating, ameliorating, preventing or curing HBV infection and related conditions. The present invention also relates to pharmaceutical compositions containing the compounds.