Imidazopyridine Kinase Inhibitors for Multi-Class RTK Targeting

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Solution Overview

Problem

Current tyrosine kinase inhibitors are inadequate in effectively targeting class 3 and class 5 receptor tyrosine kinases, particularly in treating cancers and fibrosis, and there is a need for compounds that can inhibit Pim-1 kinase activity to address leukemias and other cancers.

Innovation Solution

Development of imidazopyridine compounds with specific structural features that act as inhibitors of class 3 and class 5 receptor tyrosine kinases, including PDGFR and FLT3, and also target Pim-1 kinase, utilizing a process involving palladium catalysts and ligands for synthesis.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If current tyrosine kinase inhibitors are used, then some kinase activity is inhibited, but they are inadequate in effectively targeting class 3 and class 5 receptor tyrosine kinases

Engineering Contradiction:

Improveeffectiveness of kinase inhibitionVSAvoidability to target multiple kinase classes

Core Design Contradiction:

ReliabilityVSAdaptability or versatility

Solution Approach 1:

The imidazopyridine compound is designed to function as a universal inhibitor across multiple kinase classes (class 3 RTKs including PDGFR and FLT3, class 5 RTKs, and Pim-1), allowing a single agent to address multiple therapeutic targets that were previously requiring separate inhibitors

Inventive Principle:

Principle #6Universality (Multi-functionality)

Solution Approach 2:

The patent employs systematic variation of molecular parameters including substituents at positions 1, 2, and 7 of the imidazopyridine core, along with modifications to heterocyclic groups and linkers, to optimize binding affinity and selectivity across different kinase targets while maintaining potent inhibition

Inventive Principle:

Principle #35Parameter changes

2Adaptability or versatility

If inhibitors are designed to target multiple kinase classes, then versatility is improved, but compound complexity increases

Engineering Contradiction:

Improveability to target multiple kinase classesVSAvoidmolecular structure complexity

Core Design Contradiction:

Adaptability or versatilityVSDevice complexity

Solution Approach 1:

The inhibitor is structured as distinct functional modules: a core imidazopyridine scaffold (providing baseline kinase binding), position 1 heterocyclic substituent (enhancing selectivity), position 2 heterocyclic group (optimizing affinity), and position 7 substituted phenyl or pyridone group (expanding target coverage), allowing systematic optimization of each segment for multi-kinase inhibition

Inventive Principle:

Principle #1Segmentation

Applied Scientific Principles

This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.

Function Achieved in This Case

The imidazopyridine compounds demonstrate potent inhibition of PDGFR and FLT3, showing IC50 values less than 10 μM, and are effective in treating various cancers, fibrosis, and immune-related disorders, including leukemias and scleroderma, by attenuating kinase activity.

Implementation Method 1

utilizing a process involving palladium catalysts and ligands for synthesis

Methodology Applied

Scientific EffectCatalysis: Catalysis

Data Source

PatentEP2137184B1Imidazo[1,2-a]pyridine compounds as receptor tyrosine kinase inhibitors

Publication Date: 2013.05.08 ARRAY BIOPHARMA INC

AI summary

Compounds of Formula I: in which A, B, R1, R1a, R2, R3, R4, R5 R6, R7 and R8 have the meanings given in the specification, are receptor tyrosine inhibitors useful in the treatment of diseases mediated by class 3 and class 5 receptor tyrosine kinases. Particular compounds of this invention have also been found to be inhibitors of Pim-1.