Fused Heterocyclic Compounds as MK2 Modulators

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Solution Overview

Problem

Current treatments for inflammatory and immune diseases mediated by cytokines, such as TNFα, lack effective MK2 inhibitors with improved potency and reduced side effects.

Innovation Solution

Development of fused heterocyclic compounds, specifically those of formula (I), which act as MK2 modulators or inhibitors, administered in pharmaceutical compositions to treat diseases associated with kinase modulation, particularly targeting the p38 signaling pathway to reduce cytokine overproduction.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If current treatments for inflammatory diseases are used, then existing therapeutic options are available, but effective MK2 inhibitors with improved potency and reduced side effects are lacking

Engineering Contradiction:

Improvetherapeutic effectivenessVSAvoidside effects

Core Design Contradiction:

ReliabilityVSObject-generated harmful factors

Solution Approach 1:

The patent applies parameter changes by systematically modifying the chemical structure of pyrazolo[1,5-a]pyrimidine derivatives through various substitutions at positions R1-R10, thereby optimizing the balance between MK2 inhibition potency and reduced side effects. The structural modifications include changing substituents to achieve desired pharmacological properties while minimizing adverse effects

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The patent employs composite material principles by creating complex fused heterocyclic compounds that combine multiple functional groups and ring systems. These composite molecular structures integrate various pharmacophores to achieve selective MK2 inhibition with improved therapeutic profile compared to simpler compounds

Inventive Principle:

Principle #40Composite materials

2Productivity

If MK2 inhibitors are developed to reduce cytokine overproduction, then inflammatory response modulation is achieved, but selectivity and reduced off-target effects must be maintained

Engineering Contradiction:

Improvecytokine regulation efficiencyVSAvoidoff-target effects

Core Design Contradiction:

ProductivityVSObject-affected harmful factors

Solution Approach 1:

The patent applies local quality by introducing specific substituents at particular positions (R1-R10) on the pyrazolo[1,5-a]pyrimidine core structure. Each substitution is strategically placed to enhance MK2 binding affinity and selectivity while minimizing interactions with off-target kinases, thereby achieving localized optimization of pharmacological properties

Inventive Principle:

Principle #3Local quality

3Reliability

If new fused heterocyclic compounds are synthesized, then MK2 inhibition potency is improved, but compound complexity increases

Engineering Contradiction:

ImproveMK2 inhibition potencyVSAvoidmolecular structure complexity

Core Design Contradiction:

ReliabilityVSDevice complexity

Solution Approach 1:

The patent applies universality by designing a core pyrazolo[1,5-a]pyrimidine structure that serves as a universal scaffold for MK2 inhibition. This core structure can accommodate various substitutions (R1-R10) while maintaining the essential binding interactions with MK2, allowing a single molecular framework to fulfill multiple structural and functional requirements

Inventive Principle:

Principle #6Universality (Multi-functionality)

Data Source

PatentEP1928879B1Fused heterocyclic compounds useful as kinase modulators

Publication Date: 2013.02.13 BRISTOL MYERS SQUIBB CO

AI summary

Compounds having the formula (I), and enantiomers, and diastereomers, pharmaceutically-acceptable salts, and hydrates, thereof, (I) are useful as kinase modulators, including MK2 modulation, wherein one of E and F is a nitrogen atom and the other of E and F is a carbon atom, and Z is N or CR3, and R1, R2, R3, X and Y are as defined herein.