Evaluating Triazole-Substituted Pyrrolopyrimidines as CSF1R Inhibitors
6-Aryl-7<i>H</i>-pyrrolo[2,3-<i>d</i>]pyrimidin-4-amines have promising properties as colony-stimulating factor 1 receptor (CSF1R) inhibitors. Inspired by these antagonists, two series of 1,2,3-triazole analogues (28 compounds) were synthesized and evaluated as CSF1R inhibito...
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| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2025-06-01
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| Series: | Molecules |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1420-3049/30/12/2641 |
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| Summary: | 6-Aryl-7<i>H</i>-pyrrolo[2,3-<i>d</i>]pyrimidin-4-amines have promising properties as colony-stimulating factor 1 receptor (CSF1R) inhibitors. Inspired by these antagonists, two series of 1,2,3-triazole analogues (28 compounds) were synthesized and evaluated as CSF1R inhibitors. Enzymatic IC<sub>50</sub> profiling showed that 27 of the 28 derivatives had lower IC<sub>50</sub> than the reference drug PLX-3397. Three derivatives displayed CSF1R Ba/F3 cellular IC<sub>50</sub> well below 1 µM. Profiling of the most promising triazole analogue (compound <b>27a</b>) toward a panel of kinases reveals a high selectivity for CSF1R with respect to its family kinases, but <b>27a</b> also inhibits ABL, SRC, and YES kinases. Molecular docking of <b>27a</b> toward two CSF1R X-ray structures identified two different ligand-inverted binding poses, which triggers interest for further investigations. |
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| ISSN: | 1420-3049 |