Synthesis and Development of Highly Selective Pyrrolo2,3-dpyrimidine CSF1R Inhibitors Targeting the Autoinhibited Form

摘要

Colony-stimulating factor-1 receptor (CSF1R) is a receptortyrosinekinase that controls the differentiation and maintenance of most tissue-residentmacrophages, and the inhibition of CSF1R has been suggested as a possibletherapy for a range of human disorders. Herein, we present the synthesis,development, and structure-activity relationship of a seriesof highly selective pyrrolo-2,3-d-pyrimidines, showingsubnanomolar enzymatic inhibition of this receptor and with excellentselectivity toward other kinases in the platelet-derived growth factorreceptor (PDGFR) family. The crystal structure of the protein and 23 revealed that the binding conformation of the protein isDFG-out-like. The most promising compounds in this series were profiledfor cellular potency and subjected to pharmacokinetic profiling and in vivo stability, indicating that this compound class couldbe relevant in a potential disease setting. Additionally, these compoundsinhibited primarily the autoinhibited form of the receptor, contrastingthe behavior of pexidartinib, which could explain the exquisite selectivityof these structures.