Ketoheterocycle-based inhibitors of cathepsin K: A novel entry into the synthesis of peptidic ketoheterocycles

Ketoheterocyclic inhibitors of cathepsin K have been disclosed. SAR of potency enhancing P2–P3 groups coupled with ketoheterocyclic warheads to provide cathepsin K inhibitors have been described. In addition, a novel route to access α-ketothiazoles using a key thioamide functionality has been disclosed. The mild method employed allows for the presence of diverse functional groups, such as amide and carbamate functionalities, commonly found in protease inhibitors that have peptidomimetic scaffolds. This new method should provide a quick entry into functionally diverse protease inhibitors.

Graphical abstractKetoheterocyclic inhibitors of cathepsin K have been disclosed. SAR of potency enhancing P2–P3 groups coupled with ketoheterocyclic warheads to provide cathepsin K inhibitors have been described. In addition, a novel route to access α-ketothiazoles using a key thioamide functionality has been disclosed. The mild method employed allows for the presence of diverse functional groups, such as amide and carbamate functionalities, commonly found in protease inhibitors that have peptidomimetic scaffolds. This new method should provide a quick entry into functionally diverse protease inhibitors.Figure optionsDownload full-size imageDownload as PowerPoint slide