Quinolinone-6-sulfonamide OGT Inhibitors for Hyper-O-GlcNAcylation

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Solution Overview

Problem

Current treatments lack effective inhibitors for O-GlcNAc transferase (OGT) activity, which is implicated in various diseases such as diabetes, neurodegenerative disorders, cancers, and inflammatory diseases, leading to unmanaged hyper-O-GlcNAcylation and associated complications.

Innovation Solution

Development of compounds that inhibit OGT activity, specifically those of formula (I) and their pharmaceutical compositions, which can be administered to treat diseases associated with hyper-O-GlcNAcylation, including diabetes, insulin resistance, neurodegenerative diseases, cancers, and inflammatory diseases.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If OGT activity is not inhibited, then O-GlcNAcylation levels remain high, but this leads to disease progression including diabetes complications, neurodegenerative disorders, and inflammatory diseases

Engineering Contradiction:

Improvedisease management effectivenessVSAvoidhyper-O-GlcNAcylation

Core Design Contradiction:

ReliabilityVSObject-generated harmful factors

Solution Approach 1:

The patent extracts and isolates the harmful OGT enzymatic activity from the cellular processes, specifically targeting and inhibiting the OGT enzyme to prevent hyper-O-GlcNAcylation. This is achieved through small molecule inhibitors that bind to OGT and block its catalytic function, thereby removing the harmful effect without affecting other cellular pathways

Inventive Principle:

Principle #2Taking out (Extraction)

Solution Approach 2:

The patent changes the kinetic parameters of the OGT enzyme by introducing inhibitors that alter its catalytic activity. The inhibitors modify the enzyme's behavior by competing with substrates or allosterically regulating the enzyme, effectively changing the rate and extent of O-GlcNAcylation from pathological levels to physiological levels

Inventive Principle:

Principle #35Parameter changes

2Adaptability or versatility

If current treatments are used, then existing disease management continues, but there is lack of effective inhibitors for OGT activity

Engineering Contradiction:

Improvetreatment optionsVSAvoidOGT inhibition effectiveness

Core Design Contradiction:

Adaptability or versatilityVSReliability

Solution Approach 1:

The patent introduces small molecule compounds as intermediary substances that mediate between the OGT enzyme and its substrates. These compounds act as competitive inhibitors or allosteric modulators, interfering with the enzyme-substrate interaction and thereby providing a new mechanism for disease treatment that is distinct from existing therapies

Inventive Principle:

Principle #24Intermediary (Mediator)

Solution Approach 2:

The patent employs composite chemical structures comprising multiple functional groups working together to achieve potent and selective OGT inhibition. The inhibitors contain heterocyclic cores with various substituent groups that collectively provide binding affinity, selectivity, and pharmacological properties for effective disease treatment

Inventive Principle:

Principle #40Composite materials

Data Source

PatentUS8957075B2<i>O</i>-GlcNAc transferase inhibitors and uses thereof

Publication Date: 2015.02.17 PRESIDENT & FELLOWS OF HARVARD COLLEGE

AI summary

The present invention provides inhibitors of O-GIcNAc transferase. Typically, the inhibitors are quinolinone-6-sulfonamides. The invention also provides pharmaceutical compositions thereof and methods for using the same in diabetes and complications thereof, neurodegenerative diseases, cancers, autoimmune diseases, and inflammatory diseases.