Discovery of N-(5-amido-2-methylphenyl)-5-methylisoxazole-3-carboxamide as dual CSF-1R/c-Kit Inhibitors with improved stability and BBB permeability

• Published in: European journal of medicinal chemistry 2024-03, Vol.268, p.116253-116253, Article 116253
• Main Authors: Baek, Jihyun, Kim, Hyejin, Jun, Joonhong, Kang, Dahyun, Bae, Hyunah, Cho, Hyunwook, Hah, Jung-Mi
• Format: Article
• Language: English
• Subjects: Blood-Brain Barrier - metabolism; CSF-1R; Enzyme Inhibitors; Humans; Isoxazoles; Methyloxazole; Neurodegenerative Diseases; Neuroinflammation; Receptor Protein-Tyrosine Kinases; Receptor, Macrophage Colony-Stimulating Factor - chemistry; Receptor, Macrophage Colony-Stimulating Factor - metabolism; SAR
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2024.116253

This study explores the potential of CSF-1R inhibitors as therapeutic agents for neurodegenerative diseases. CSF-1R, a receptor tyrosine kinase primarily expressed in macrophage lineages, plays a pivotal role in regulating various cellular processes. Recent research highlights the significance of CSF-1R inhibition in mitigating neuroinflammation, particularly in Alzheimer's disease, where microglial overactivation contributes to neurodegeneration. The research reveals a series of N-(5-amido-2-methylphenyl)-5-methylisoxazole-3-carboxamide CSF-1R inhibitors, where compounds 7d, 7e, and 9a exhibit outstanding inhibitory activities and selectivity, with IC50 values of 33, 31, and 64 nM, respectively. These most promising compounds in this series were profiled for cellular potency and subjected to in vitro pharmacokinetic profiling. These inhibitors exhibit minimal cytotoxicity, even at higher concentrations, and possess promising blood-brain barrier permeability, making them potential candidates for central nervous system diseases. The investigation into the in vitro ADME properties, including plasma and microsomal stability, reveals that these CSF-1R inhibitors maintain their structural integrity and plasma concentration. This resilience positions them for further development as therapeutic agents for neurodegenerative diseases. [Display omitted] •N-(5-amido-2-methylphenyl)-5-methylisoxazole-3-carboxamide derivatives were designed as CSF1R inhibitors.•Nanomolar inhibitory effect against CSF1R were observed in the compounds 7d and 9a havng c-Kit inhibitory effects.•Compounds 7d and 9a exhibited excellent kinase selectivity and cellular effect.•Compounds 7d and 9a exhibited strong BBB permeability, good MS and PS, making them potential anti-neuroinflammation agents.