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which of the cathepsins would be an appropriate target. A breakthrough in the field
was achieved when cathepsin K was identified as the major bone-degrading protease
in osteoclasts. Here, a defined target with a clear pathophysiological function became
available. Serious efforts in cathepsin K inhibitor design led to the generation of
highly specific cathepsin K inhibitors with excellent pharmacodynamic features
(Deaton and Tavares 2005 ; Kim and Tasker 2006 ; Yamashita and Dodds 2000 ). At
least four different cathepsin K inhibitors entered clinical trials with one compound,
odanacatib, presently in phase III clinical testing (reviewed in Bromme and Lecaille
2009 ;RodanandDuong 2008 ). Phase II clinical evaluation of odanacatib demon-
strated a dose-dependent reduction in bone resorption markers and an increase in
bone mineral density (BMD) at the total hip, lumbar spine, and femoral neck in
postmenopausal women with low BMD when given at doses of 10, 25, or 50 mg per
week. BMD increased for 24 months of the 2-year study (Rodan and Duong 2008 ). It
should be noted that at least one clinical trial was terminated due to potentially
adverse skin and lung side effects of the cathepsin K inhibitor, balicatib. Balicatib,
similar to odancatib, is a nitrile-based peptide derivative. Though it showed a similar
high selectivity for cathepsin K as odanacatib in in vitro enzyme assays, it lost
significant selectivity in cell-based assays due to its lysosomotropic properties
(Falgueyret et al. 2005 ). An increased accumulation of a cathepsin inhibitor in the
acidic lysosome/endosome compartment may lead to the inhibition of related cyste-
ine proteases such as cathepsins L, S, and V. In contrast, odanacatib is a nonbasic
inhibitor which still maintains its potency and selectivity against individual cathe-
psins as well as their efficacy in cell-based assays (Desmarais et al. 2008 ). Besides
potential off-target effects of lysosomotropic inhibitors, their lysosomal accumula-
tion may also inhibit cathepsin K in cells other than osteoclasts such as fibroblasts.
This may account for the adverse (fibrotic?) side effects of balicatib in skin and lungs.
Cathepsin K inhibitors may also be effective in the treatment of rheumatoid and
osteoarthritis, certain bone cancers, and atherosclerosis. In all these diseases, cathep-
sin K plays a critical role in ECM degradation (for review see Podgorski 2009 ;
Yasuda et al. 2005 ). It should be mentioned that cathepsin inhibitors, in particular
cathepsin S inhibitors, are in preclinical trials for the treatment of immune system-
related diseases including rheumatoid arthritis. Here, the pharmacological target is
not the degradation of ECM by cathepsin S but its function (and potentially those of
cathepsins L and V as well) in antigen processing and presentation (Yasuda et al.
2005 ). However, cathepsin S inhibitors may also be tested to control cathepsin
S-mediated ECM degradation in the near future, as new research supports a direct
role of this enzyme in extracellular matrix destruction (de Nooijer et al. 2009 ).
2.7 Conclusion
Cysteine cathepsins are known as lysosomal proteases responsible for the degrada-
tion of intracellular and endocytosed proteins. Their enzymatic characteristics
make them well adjusted to the acidic and reducing environment of lysosomes,
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