Colony-stimulating factor-1 receptor (CSF1R) is a receptor
tyrosine
kinase that controls the differentiation and maintenance of most tissue-resident
macrophages, and the inhibition of CSF1R has been suggested as a possible
therapy for a range of human disorders. Herein, we present the synthesis,
development, and structure–activity relationship of a series
of highly selective pyrrolo[2,3-d]pyrimidines, showing
subnanomolar enzymatic inhibition of this receptor and with excellent
selectivity toward other kinases in the platelet-derived growth factor
receptor (PDGFR) family. The crystal structure of the protein and23revealed that the binding conformation of the protein is
DFG-out-like. The most promising compounds in this series were profiled
for cellular potency and subjected to pharmacokinetic profiling andin vivostability, indicating that this compound class could
be relevant in a potential disease setting. Additionally, these compounds
inhibited primarily the autoinhibited form of the receptor, contrasting
the behavior of pexidartinib, which could explain the exquisite selectivity
of these structures.