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Hurdles in the Drug Discovery of Cathepsin K Inhibitors

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There were many hurdles in the drug discovery of cathepsin K inhibitors such as species differences not only in bone metabolism but also in amino acid sequences in the critical site of the target enzyme, discrepancies between PK/PD due to unique tissue distribution of the inhibitor affecting both efficacy and side effects originated from a characteristic intracellular or tissue distribution of some classes of compounds. The value of this new therapeutic approach over the launched indirect competitors should be further clarified from the efficacy and side effect point of view. The cathepsin K inhibitor drug discovery was initiated based on a strong and osteoclast-specific expression of this enzyme. However, the tissues and cells expressing cathepsin K have been expanding as the investigation on pathological conditions progressed with respect to side effects as well as new possible indications.
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Keywords: Bone resorption; Cathepsin K inhibitors; On- and Off-target Side Effects; Osteoclasts; Osteoporosis; PK/PD; Species differences

Document Type: Research Article

Affiliations: Novartis Institutes for BioMedical Research Cambridge, 100 Technology Square, Cambridge, MA 02139, USA.

Publication date: May 1, 2010

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