ERK Inhibitor Salt Forms for Solubility and Stability

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Solution Overview

Problem

Current therapeutic agents are inadequate in effectively targeting and inhibiting the ERK/MAPK pathway, which is frequently activated in various tumors, leading to uncontrolled cell proliferation and tumor growth.

Innovation Solution

Development of novel salt forms and freebase forms of ERK kinase inhibitors, such as compound 1, which exhibit covalent and irreversible inhibition of ERK1 and ERK2 kinases, improving aqueous solubility, stability, and ease of formulation.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If conventional therapeutic agents are used to target the ERK/MAPK pathway, then the treatment approach is simple and well-established, but the agents are inadequate in effectively inhibiting ERK1 and ERK2 kinases, leading to poor therapeutic outcomes

Engineering Contradiction:

Improveeffectiveness of ERK inhibitionVSAvoidcomplexity of developing novel inhibitor forms

Core Design Contradiction:

ReliabilityVSEase of manufacture

Solution Approach 1:

The patent applies parameter changes by developing novel salt forms and freebase forms of ERK inhibitors, altering the physical and chemical parameters of the compounds to improve their pharmacological properties. This includes modifying solubility, stability, and bioavailability parameters to enhance therapeutic effectiveness while maintaining the core inhibitory mechanism against ERK1 and ERK2 kinases

Inventive Principle:

Principle #35Parameter changes

2Stability of the object's composition

If novel salt forms and freebase forms of ERK inhibitors are developed, then aqueous solubility and stability are improved, but the complexity of formulation and manufacturing increases

Engineering Contradiction:

Improvestability of ERK inhibitorVSAvoidcomplexity of formulation

Core Design Contradiction:

Stability of the object's compositionVSDevice complexity

Solution Approach 1:

The patent applies segmentation by separating the ERK inhibitor compound into distinct crystalline forms (Form 1, Form 2, Form 3, etc.) and salt forms. Each form is characterized and optimized for specific properties such as solubility and stability, allowing selective use of different forms based on therapeutic requirements while simplifying formulation development for each specific form

Inventive Principle:

Principle #1Segmentation

3Duration of action of moving object

If covalent and irreversible inhibition of ERK1 and ERK2 is achieved, then the duration of action is extended, but the risk of off-target effects and toxicity may increase

Engineering Contradiction:

Improveduration of ERK inhibitionVSAvoidoff-target effects and toxicity

Core Design Contradiction:

Duration of action of moving objectVSObject-affected harmful factors

Solution Approach 1:

The patent applies local quality by designing inhibitors with specific molecular structures that exhibit selective affinity for ERK1 and ERK2 kinases. The local chemical properties of the inhibitor molecules are optimized to interact preferentially with the active sites of ERK1/ERK2, thereby extending duration of action while minimizing off-target effects through enhanced selectivity

Inventive Principle:

Principle #3Local quality

Data Source

PatentEP3179858B1Forms and compositions of an ERK inhibitor

Publication Date: 2019.05.15 CELGENE CAR LLC

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AI summary

The present invention provides compounds, compositions thereof, and methods of using the same for the inhibition of one or both of ERK1 and ERK2.