Propionic Acid Derivatives for Selective Integrin α4β7 Inhibition

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Solution Overview

Problem

Current treatments for inflammatory bowel diseases related to integrin α4β7 activity lack specific small-molecule compounds, and existing therapies like natalizumab have significant side effects.

Innovation Solution

Development of novel integrin α4β7 inhibitors with improved selectivity, stability, and safety profiles, specifically targeting integrin α4β7 activity to treat inflammatory bowel diseases.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If natalizumab (monoclonal antibody targeting α4 subunit) is used to treat Crohn's disease, then therapeutic effect is achieved, but side effect of PML occurs

Engineering Contradiction:

Improvetherapeutic effectVSAvoidPML side effect

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The patent replaces the expensive, long-acting monoclonal antibody (natalizumab) with smaller, short-acting small-molecule compounds. These small molecules can be administered orally and have shorter half-lives, allowing for safer therapeutic windows that reduce the risk of severe side effects like PML while maintaining therapeutic efficacy through repeated dosing.

Inventive Principle:

Principle #27Cheap short-living objects (Disposable)

Solution Approach 2:

The patent changes the molecular parameters from large protein-based therapeutics to small-molecule compounds with different pharmacokinetic properties. This includes changing molecular weight, oral bioavailability, metabolism pathways, and elimination rates, thereby achieving similar therapeutic effects with improved safety profiles.

Inventive Principle:

Principle #35Parameter changes

2Object-affected harmful factors

If small-molecule compounds targeting integrin α4β7 are developed, then safety is improved compared to natalizumab, but selectivity for α4β1/α4β7 needs to be enhanced

Engineering Contradiction:

Improvesafety profileVSAvoidselectivity

Core Design Contradiction:

Object-affected harmful factorsVSManufacturing precision

Solution Approach 1:

The patent applies local quality by designing small-molecule compounds that specifically target the α4β7 integrin interface with unique spatial and chemical characteristics. The molecules are engineered to interact with specific residues or conformational states of α4β7 that are distinct from α4β1, thereby achieving high selectivity at the molecular interaction level while maintaining safety.

Inventive Principle:

Principle #3Local quality

3Reliability

If compounds with improved pharmacokinetic properties are designed, then drug efficacy is enhanced, but complexity of compound structure increases

Engineering Contradiction:

Improvepharmacokinetic propertiesVSAvoidcompound structure

Core Design Contradiction:

ReliabilityVSDevice complexity

Solution Approach 1:

The patent segments the complex pharmacokinetic requirements into manageable molecular features. Instead of designing one highly complex molecule, the approach divides the therapeutic strategy into a series of smaller molecular building blocks that can be combined or selected to achieve desired absorption, distribution, metabolism, and excretion properties, thereby managing structural complexity.

Inventive Principle:

Principle #1Segmentation

Data Source

PatentEP4585587A1Propionic acid derivative and use thereof in medicine

Publication Date: 2025.07.16 TIBET HAISCO PHARM CO LTD

AI summary

A compound of general formula (I) or a stereoisomer, mesomer/racemate, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt, or co-crystal thereof, an intermediate thereof, a preparation method therefor, and a use in the preparation of a drug for treating diseases related to integrin α4β7 activity or expression.