Novel, potent P2–P3 pyrrolidine derivatives of ketoamide-based cathepsin K inhibitors

Starting from a potent pantolactone ketoamide cathepsin K inhibitor discovered from structural screening, conversion of the lactone scaffold to a pyrrolidine scaffold allowed exploration of the S3 subsite of cathepsin K. Manipulation of P3 and P1′P1′ groups afforded potent inhibitors with drug-like properties.

Graphical abstractStarting from a potent pantolactone ketoamide cathepsin K inhibitor derived from structural screening, conversion of the lactone scaffold to a pyrrolidine scaffold allowed exploration of the S3 subsite of cathepsin K. Manipulation of P3 and P1′P1′ groups afforded potent inhibitors with drug-like propertiesFigure optionsDownload full-size imageDownload as PowerPoint slide