Sulfonamide Derivatives for Selective Alpha4beta7 Integrin Inhibition

Solution Overview

Problem

Current orally administrable compounds with α4 integrin-inhibitory action are not highly selective for α4β1 and α4β7 integrins, limiting their effectiveness in treating inflammatory diseases associated with α4β7 integrin-dependent adhesion processes.

Innovation Solution

Development of sulfonamide derivatives with a specific chemical structure featuring a sulfonamide group and a phenyl or heterocyclic group as substituents, which exhibit selective α4 integrin inhibition, particularly targeting α4β7 integrins.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Ease of operation

If phenylalanine derivatives are used as orally administrable compounds with α4 integrin-inhibitory action, then the compounds can be administered orally and show integrin inhibition, but the compounds lack high selectivity for α4β1 and α4β7 integrins

Engineering Contradiction:

Improveoral administrabilityVSAvoidselectivity for α4β1 and α4β7 integrins

Core Design Contradiction:

Ease of operationVSManufacturing precision

Solution Approach 1:

The invention introduces specific substituent groups (sulfonamide group with phenyl or heterocyclic group) at particular positions (terminal or penultimate carbon atoms) of the phenylalanine derivative backbone. This localized structural modification enhances selectivity for α4β7 integrin while maintaining oral administrability, resolving the contradiction between ease of operation and manufacturing precision.

Inventive Principle:

Principle #3Local quality

Solution Approach 2:

The invention modifies chemical structural parameters of the phenylalanine derivative by introducing specific substituents (sulfonamide group with phenyl or heterocyclic group) at defined positions. These parameter changes result in compounds with enhanced selectivity for α4β7 integrin compared to prior art compounds, while preserving oral administrability.

Inventive Principle:

Principle #35Parameter changes

2Reliability

If compounds with α4 integrin-inhibitory action are developed, then inflammatory diseases can be treated, but the compounds do not show high selectivity particularly for α4β7 integrins

Engineering Contradiction:

Improveeffectiveness in treating inflammatory diseasesVSAvoidselectivity for α4β7 integrins

Core Design Contradiction:

ReliabilityVSManufacturing precision

Solution Approach 1:

The invention introduces specific substituent groups (sulfonamide group with phenyl or heterocyclic group) at particular positions (terminal or penultimate carbon atoms) of the phenylalanine derivative backbone. This localized structural modification enhances selectivity for α4β7 integrin while maintaining oral administrability, resolving the contradiction between ease of operation and manufacturing precision.

Inventive Principle:

Principle #3Local quality

Solution Approach 2:

The invention modifies chemical structural parameters of the phenylalanine derivative by introducing specific substituents (sulfonamide group with phenyl or heterocyclic group) at defined positions. These parameter changes result in compounds with enhanced selectivity for α4β7 integrin compared to prior art compounds, while preserving oral administrability.

Inventive Principle:

Principle #35Parameter changes

Data Source

PatentUS9533985B2Sulfonamide derivative and medicinal use thereof

Publication Date: 2017.01.03 EA PHARMA CO LTD

AI summary

Sulfonamide compounds of a specific chemical structure in which a sulfonamide group having, as a substituent, a phenyl group or a heterocyclic group having a hetero atom(s) as a constituent element(s) is present at its terminal, and pharmaceutically acceptable salts thereof. These compounds are novel compounds having excellent α4 integrin-inhibitory action. The compounds have formulae represented by: