Lysosomotropism of basic cathepsin K inhibitors contributes to increased cellular potencies against off-target cathepsins and reduced functional selectivity.

@article{Falgueyret2005LysosomotropismOB,
  title={Lysosomotropism of basic cathepsin K inhibitors contributes to increased cellular potencies against off-target cathepsins and reduced functional selectivity.},
  author={J. P. Falgueyret and Sylvie Desmarais and Renata Oballa and W. Cameron Black and Wanda A Cromlish and Karine Khougaz and Sonia Lamontagne and Fr{\'e}d{\'e}ric Mass{\'e} and Denis Riendeau and Sylvie Toulmond and Maida Percival},
  journal={Journal of medicinal chemistry},
  year={2005},
  volume={48 24},
  pages={7535-43}
}
The lysosomal cysteine protease cathepsin K is a target for osteoporosis therapy. The aryl-piperazine-containing cathepsin K inhibitor CRA-013783/L-006235 (1) displays greater than 4000-fold selectivity against the lysosomal/endosomal antitargets cathepsin B, L, and S. However, 1 and other aryl-piperazine-containing analogues, including balicatib (10), are approximately 10-100-fold more potent in cell-based enzyme occupancy assays than against each purified enzyme. This phenomenon arises from… CONTINUE READING