Potent dipeptidylketone inhibitors of the cysteine protease cathepsin K

Cathepsin K (EC 3.4.22.38) is a cysteine protease of the papain superfamily which is selectively expressed within the osteoclast. Several lines of evi dence have pointed to the fact that this protease may play an important rol e in the degradation of the bone matrix. Potent and selective inhibitors of cathepsin K could be important therapeutic agents for the control of exces sive bone resorption. Recently a series of peptide aldehydes have been show n to be potent inhibitors of cathepsin K. In an effort to design more selec tive and metabolically stable inhibitors of cathepsin K, a series of electr onically attenuated alkoxymethylketones and thiomethylketones inhibitors ha ve been synthesized. The X-ray co-crystal structure of one of these analogu es in complex with cathepsin K shows the inhibitor binding in the primed si de of the enzyme active site with a covalent interaction between the active site cysteine 25 and the carbonyl carbon of the inhibitor. (C) 1999 Elsevi er Science Ltd. All rights reserved.