SAR-driven optimization of 2-amino-oxazole-based dual CSF-1R/c-Kit inhibitors for neuroinflammation

초록

Colony-stimulating factor-1 receptor (CSF-1R) is a class III receptor tyrosine kinase that regulates monocyte/macrophage lineage cells, including microglia, and has emerged as an attractive target for neuroinflammation-associated neurodegenerative diseases. Inspired by the clinical relevance of dual CSF-1R/c-Kit inhibition and building upon our previously reported 5-methylisoxazole-based lead scaffold, we designed and synthesized a new series of 2-amino-oxazole-based inhibitors by replacing the original 5-methylisoxazole hinge-binding motif with a 2-amino-oxazole core, thereby introducing an additional hydrogen-bond donor. Structure–activity relationship studies revealed that CSF-1R/c-Kit inhibitory activity was strongly influenced by N-substitution, amide bond directionality, and the spatial arrangement of basic amine-containing R groups. Notably, modification of the terminal aryl substitution pattern from 1,3,5 to 1,3,4 enabled improved positioning of pendant amines and afforded several low-nanomolar CSF-1R/c-Kit inhibitors. Integrated biochemical, cellular, kinome, and in vitro ADME profiling identified 12l and 11o as the most promising lead candidates. In SIM-A9 microglial cells, both compounds suppressed CSF-1-induced ERK phosphorylation, a downstream readout of CSF-1R signaling. Compound 12l showed potent dual CSF-1R/c-Kit inhibition, suppression of CSF-1-induced ERK phosphorylation, favorable microsomal and plasma stability, high BBB-PAMPA permeability, and a cleaner kinome selectivity profile. Compound 11o exhibited particularly strong c-Kit inhibition, suppression of CSF-1-induced ERK phosphorylation in SIM-A9 cells, and favorable ADME properties. These findings identify 12l and 11o as promising dual CSF-1R/c-Kit inhibitor leads for further development toward neuroinflammation-associated neurodegenerative diseases. © 2026 Elsevier Masson SAS

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