N-hydroxyformamide Derivative for ADAM17 and ADAM10 Inhibition

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Solution Overview

Problem

Current treatments for inflammatory disorders and cancers lack effective inhibitors for ADAM17 and ADAM10, which are involved in various pathological conditions, including rheumatoid arthritis, systemic lupus erythematosus, and cancer progression.

Innovation Solution

A novel N-hydroxyformamide derivative with a specific structure is developed, exhibiting excellent ADAM17-inhibitory activity and also inhibiting ADAM10, providing a therapeutic agent for these conditions.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If conventional treatments are used for inflammatory disorders and cancers, then current standard therapies are applied, but effective inhibition of ADAM17 and ADAM10 is not achieved

Engineering Contradiction:

Improvetherapeutic efficacyVSAvoidinhibitor coverage

Core Design Contradiction:

ReliabilityVSAdaptability or versatility

Solution Approach 1:

The N-hydroxyformamide derivative is designed to inhibit multiple ADAM family members (ADAM17, ADAM10, and other ADAM proteins) with a single compound structure, providing broad-spectrum protease inhibition. This multi-functional approach allows one agent to address multiple pathological processes involving different ADAM enzymes, thereby improving both therapeutic efficacy and inhibitor coverage simultaneously

Inventive Principle:

Principle #6Universality (Multi-functionality)

2Adaptability or versatility

If ADAM17 inhibitors are developed to treat inflammatory disorders, then rheumatoid arthritis and systemic lupus erythematosus can be treated, but ADAM10-mediated pathological processes remain unaddressed

Engineering Contradiction:

Improveprotease inhibition scopeVSAvoidpathological condition coverage

Core Design Contradiction:

Adaptability or versatilityVSReliability

Solution Approach 1:

The compound exhibits broad inhibitory activity against multiple ADAM family members including both ADAM17 and ADAM10. This universal inhibition capability ensures comprehensive coverage of pathological conditions mediated by different ADAM enzymes, addressing both inflammatory disorders and cancer progression that involve these proteases

Inventive Principle:

Principle #6Universality (Multi-functionality)

3Object-affected harmful factors

If TNF-α conversion is inhibited to reduce inflammatory cytokine hypersecretion, then inflammatory responses are reduced, but cell apoptosis and signal transduction obstruction may occur

Engineering Contradiction:

Improveinflammatory cytokine hypersecretionVSAvoidcell apoptosis and signal transduction obstruction

Core Design Contradiction:

Object-affected harmful factorsVSObject-generated harmful factors

Solution Approach 1:

The N-hydroxyformamide derivative modifies the inhibition parameters by targeting the catalytic zinc site of ADAM17 with high specificity, controlling the degree and kinetics of enzyme inhibition. This precise parameter control allows suppression of pathological TNF-α conversion while minimizing off-target effects that could lead to cell apoptosis or signal transduction obstruction

Inventive Principle:

Principle #35Parameter changes

Data Source

PatentEP2597084B1N-hydroxyformamide derivative and pharmaceutical containing same

Publication Date: 2016.06.29 KAKEN PHARMA CO LTD

AI summary

A compound represented by the following general formula (I) which has ADAM17 inhibitory activity, or a salt thereof, or a solvate thereof: wherein X represents a phenylene group; Y represents a hydrogen atom, -(CH2)mR1 or the like; R1 represents -NR5COR2, -NR5SO2R2 or -NR3R4; R2 represents a C1-C6 alkyl group, an aryl group, or a C1-C6 alkoxy group; R3 and R4 represent a C1-C6 alkyl group and the like; R5 represents a hydrogen atom or a C1-C6 alkyl group or the like; m indicates an integer of from 0 to 4; and Z represents a hydrogen atom or a C1-C6 alkyl group.