Sulfonamide Derivatives for Ocular Inflammation

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Solution Overview

Problem

Current broad spectrum chemokine inhibitors, primarily peptides, have limitations such as low potency, poor pharmacokinetics, and instability in vivo, making them unsuitable for long-term therapeutic use in ocular inflammatory diseases, and systemic administration risks deleterious side effects due to systemic anti-inflammatory activity.

Innovation Solution

Development of novel sulfur derivatives that act as potent and selective chemokine receptor modulators, including compounds of Formula I, which can be used topically to treat ocular inflammatory diseases by modulating chemokine receptors, thereby offering a more stable and localized treatment option.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If peptide-based broad spectrum chemokine inhibitors are used, then chemokine receptor modulation is achieved, but potency is low and stability in vivo is poor

Engineering Contradiction:

Improvestability in vivoVSAvoidpotency

Core Design Contradiction:

ReliabilityVSProductivity

Solution Approach 1:

The patent transforms the chemical structure from peptide-based to small molecule sulfonamide derivatives, fundamentally changing the molecular parameters to achieve both high potency (nanomolar IC50 values) and improved stability in vivo while maintaining broad spectrum chemokine receptor inhibition

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The sulfonamide derivative compounds incorporate multiple structural components (heteroaryl groups, sulfur-containing moieties, aromatic rings) into a composite molecular structure that combines the benefits of peptide-based specificity with small molecule stability and potency

Inventive Principle:

Principle #40Composite materials

2Duration of action of moving object

If peptide-based chemokine inhibitors are used for long-term therapeutic use, then chemokine receptor modulation is achieved, but pharmacokinetics are poor

Engineering Contradiction:

Improveduration of therapeutic actionVSAvoidpharmacokinetics

Core Design Contradiction:

Duration of action of moving objectVSProductivity

Solution Approach 1:

The transition from peptide to small molecule sulfonamide structure fundamentally alters pharmacokinetic parameters including absorption, distribution, metabolism, and excretion (ADME) properties, enabling longer duration of action and improved suitability for chronic ocular disease treatment

Inventive Principle:

Principle #35Parameter changes

3Reliability

If systemic administration of broad spectrum chemokine inhibitors is performed, then chemokine receptor modulation is achieved, but systemic anti-inflammatory activity causes deleterious side effects

Engineering Contradiction:

Improvetherapeutic efficacyVSAvoidsystemic side effects

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The patent enables localized ocular administration of sulfonamide derivatives, concentrating the therapeutic effect in the eye while minimizing systemic exposure and associated side effects, thereby achieving local quality improvement in the treatment profile

Inventive Principle:

Principle #3Local quality

Data Source

PatentEP2970239B1Sulfonamide derivatives as chemokine receptor modulators

Publication Date: 2018.10.10 ALLERGAN INC

AI summary

The present invention relates to novel pyridine or pyrimidine derivatives of the Formula I, processes for preparing them, pharmaceutical compositions containing them and their use as pharmaceuticals as modulators of chemokine receptors. The invention relates specifically to the use of these compounds and their pharmaceutical compositions to treat disorders associated with chemokine receptor modulation, such as ocular inflammatory diseases or skin inflammatory diseases.