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When evaluating inhibitors of lysosomal enzymes, such as the cathepsins, this physical property can have a dramatic impact on the functional selectivity of the test compounds. A basic P3 substituent in cathepsin K inhibitors provides a means of achieving potent and selective enzyme inhibition. To evaluate the whole\u2010cell selectivity of the basic cathepsin K inhibitor L\u2010006235, we identified the irreversible pan\u2010selective cathepsin probe BIL\u2010DMK and used it to design whole\u2010cell enzyme\u2010occupancy assays. These cell\u2010based assays showed a dramatic reduction in selectivity against cathepsins B, L, and S relative to the selectivities observed in enzyme assays. Two\u2010photon confocal fluorescence microscopy showed punctated subcellular localization of L\u2010006235, which colocalized with BODIPY\u2010labelled Lysotracker, consistent with compound lysosomotropism. To address this potential problem, a series of potent cathepsin K inhibitors was developed by replacing the P2\uf8ffP3 amide bond with a metabolically stable trifluoroethylamine moiety. X\u2010ray crystallography has identified the binding of this functional group to active\u2010site residues in cathepsin K. This modification resulted in increased potency and selectivity that allowed the removal of the basic P3 substituent. The resulting nonbasic inhibitor L\u2010873724 is a 0.2 n<jats:sc>M<\/jats:sc> inhibitor of cathepsin K with cathepsin B, L, and S potencies that were not shifted between purified enzyme and whole\u2010cell assays; thus indicating that this compound is not lysosomotropic. L\u2010873724 exhibits excellent pharmacokinetics and is orally active in a monkey model of osteoporosis at 3 mg\u2009kg<jats:sup>\u22121<\/jats:sup> q.d.<\/jats:p>","DOI":"10.1002\/cbic.200600149","type":"journal-article","created":{"date-parts":[[2006,8,21]],"date-time":"2006-08-21T07:16:30Z","timestamp":1156144590000},"page":"1525-1535","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":64,"title":["The Consequences of Lysosomotropism on the Design of Selective Cathepsin K Inhibitors"],"prefix":"10.1002","volume":"7","author":[{"given":"W. Cameron","family":"Black","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M. 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