Small-molecule inhibitor: L-235

Name

History: CRA-013783 was described (as 39n) by Palmer et al. ( 2005).
Peptidases inhibited: CRA-013783 is highly selective for the inhibition of cathepsin K. K_i values for cathepsin B, cathepsin L and cathepsin S were at least 4000-fold greater.
Mechanism: Inhibition is reversible. Rabbit cathepsin K was inhibited with K_i 0.29 nM, and the mode of binding of the inhibitor to the surface of the cathepsin K molecule has been shown by X-ray crystallography (Palmer et al., 2005).
Pharmaceutical relevance: Cathepsin K is an important mediator of collagen degradation in osteoclastic bone resorption, and oral dosing of ovariectomised rhesus monkeys with CRA-013783 led to a large reduction in collagen breakdown. The in vivo distribution and selectivity of the compound are affected by its basic, lipophilic nature (Falgueyret et al., 2005).

Comment: The design of this substituted aminoacetonitrile started from Z-Leu-Gly-CN, which inhibited cathepsin K with 35 nM K_i, but had poor selectivity.
Reviews: Palmer et al. ( 2005)