Cyclic ketone inhibitors of the cysteine protease cathepsin K

Cathepsin K (EC 3.4.22.38), a cysteine protease of the papain superfamily, is predominantly expressed in osteoclasts and has been postulated as a targ et for the treatment of osteoporosis. Crystallographic and structure-activi ty studies on a series of acyclic ketone-based inhibitors of cathepsin K ha ve led to the design and identification of two series of cyclic ketone inhi bitors. The mode of binding for four of these cyclic and acyclic inhibitors to cathepsin K is discussed and compared. All of the structures are consis tent with addition of the active site thiol to the ketone of the inhibitors with the formation of a hemithioketal. Cocrystallization of the C-3 diaste reomeric 3-amidotetrahydrofuran-4-one analogue 16 with cathepsin K showed t he inhibitor to occupy the unprimed side of the active site with the 3S dia stereomer preferred. This C-3 stereochemical preference is in contrast to t he X-ray cocrystal structures of the 3-amidopyrrolidin-4-one inhibitors 29 and 33 which show these inhibitors to prefer binding of the 3R diastereomer . The 3-amidopyrrolidin-4-one inhibitors were bound in the active site of t he enzyme in two alternate directions. Epimerization issues associated with the labile a-amino ketone diastereomeric center contained within these inh ibitor classes has proven to limit their utility despite promising pharmaco kinetics displayed in both series of compounds.