CSF-1R Inhibitor Scaffolds With C-4 Substitution Selectivity

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Solution Overview

Problem

Existing inhibitors for the Colony stimulating factor-1 receptor (CSF-1R) exhibit significant side effects and lack selectivity, limiting their therapeutic potential in treating diseases such as cancers, bone disorders, neurological diseases, and inflammatory disorders.

Innovation Solution

Development of pyrrolopyrimidines and purines with specific substitutions at the C-4 nitrogen or C-6 nitrogen, enhancing selectivity towards CSF-1R inhibition by blocking EGFR activity and improving solubility and bioavailability through polar R1 groups.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If substitution at the C-4 nitrogen is performed to convert compounds from EGFR inhibitors to CSF-1R inhibitors, then selectivity towards CSF-1R is improved, but EGFR activity is blocked

Engineering Contradiction:

ImproveselectivityVSAvoidside effects

Core Design Contradiction:

ReliabilityVSObject-generated harmful factors

Solution Approach 1:

The patent applies local quality by making a specific modification at the C-4 nitrogen position of the pyrrolopyrimidine core structure. This localized substitution (with methyl, ethyl, or other alkyl groups) changes the chemical properties at that specific site, enabling selective binding to CSF-1R while preventing binding to EGFR. The modification is confined to a specific location in the molecule rather than changing the entire structure, thus achieving selectivity with minimal impact on overall molecular function.

Inventive Principle:

Principle #3Local quality

2Reliability

If existing CSF-1R inhibitors are used to treat diseases, then therapeutic potential is achieved, but significant side effects occur due to lack of selectivity

Engineering Contradiction:

Improvetherapeutic potentialVSAvoidside effects

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The patent employs parameter changes by systematically varying the substituents at the C-4 nitrogen position (methyl, ethyl, isopropyl, cyclopropyl, etc.) and at other positions on the molecule. These parameter changes optimize the balance between CSF-1R binding affinity and selectivity. By adjusting these chemical parameters, the compounds achieve potent inhibition of CSF-1R (IC50 values in the nanomolar range) while maintaining selectivity against EGFR and other kinases, thereby reducing side effects.

Inventive Principle:

Principle #35Parameter changes

3Ease of operation

If polar R1 groups are introduced to improve solubility and bioavailability, then solubility is enhanced, but molecular complexity increases

Engineering Contradiction:

ImprovesolubilityVSAvoidmolecular complexity

Core Design Contradiction:

Ease of operationVSDevice complexity

Solution Approach 1:

The patent applies segmentation by dividing the molecule into distinct functional regions: the core pyrrolopyrimidine structure, the C-4 nitrogen substituent, and the R1 groups at various positions. The R1 groups (which can be hydroxyl, alkoxy, carboxylic acid, amino, or other polar groups) are introduced at specific positions to enhance solubility without requiring complex modifications throughout the entire molecule. This segmented approach allows independent optimization of solubility properties while maintaining the core inhibitory activity.

Inventive Principle:

Principle #1Segmentation

Data Source

PatentUS20250353857A1Compound active as inhibitor of colony stimulation factor-1 receptor (CSF-1 r)

Publication Date: 2025.11.20 NORWEGIAN UNIVERSITY OF SCIENCE AND TECHNOLOGY (NTNU)

AI summary

The present invention relates to new pyrrolopyrimidines and purines which surprisingly act as CSF-1R inhibitors, to processes for making these compounds, and to uses thereof.