Discovery of oxazole-capped 4-phenoxypiperidine CSF1R type II inhibitors with potent in vivo anti-rheumatoid arthritis activity.

Colony-stimulating factor 1 receptor (CSF-1R) is a key target for regulating macrophage function and mediating the inflammatory response. Blocking CSF-1/CSF-1R signaling pathway and its downstream AKT cascade can effectively inhibit the release of downstream proinflammatory cytokines, which provides a promising therapeutic strategy for controlling inflammation. Based on structure-guided drug design and systematic structure-activity relationship (SAR) optimization, we developed a series of novel (4-phenoxy) piperidine-1-methanone derivatives, among which compound 11g potently inhibited CSF-1R kinase with an IC50 value of 17.2 nM. In addition, compound 11g exhibits a favorable selectivity profile in protein kinases at 1 μM. Mechanistic studies demonstrate that Compound 11g directly disrupts CSF-1/CSF-1R signaling, leading to marked suppression of AKT phosphorylation, as reflected by diminished p-CSF-1R and p-AKT levels in RAW264.7 macrophages. This pathway-specific blockade translates into a dose-dependent inhibition of pro-inflammatory cytokine production, including TNF-α, IL-6, and IL-1β. In vivo, compound 11g showed acceptable pharmacokinetic properties and demonstrated remarkable anti-rheumatoid arthritis effects in the adjuvant-induced arthritis (AIA) model. These findings highlight the therapeutic potential of targeting the complete CSF-1R-AKT pathway for rheumatoid arthritis treatment and establish compound 11g as a promising lead candidate for further development.