Cathepsin K is an osteoclast-derived
cysteine protease that has been implicated as playing a major role in
bone resorption. A substantial body of evidence indicates that
cathepsin K is critical in osteoclast-mediated
bone resorption and suggests that its pharmacological inhibition should result in inhibition of
bone resorption in vivo. Here we report the pharmacological characterization of
SB-462795 (
relacatib) as a potent and orally bioavailable small molecule inhibitor of
cathepsin K that inhibits
bone resorption both in vitro in human tissue and in vivo in cynomolgus monkeys.
SB-462795 is a potent inhibitor of human
cathepsins K, L, and V (K(i, app)=41, 68, and 53 pM, respectively) that exhibits 39-300-fold selectivity over other
cathepsins.
SB-462795 inhibited endogenous
cathepsin K in situ in human osteoclasts and human osteoclast-mediated
bone resorption with IC50 values of approximately 45 nM and approximately 70 nM, respectively. The anti-resorptive potential of
SB-462795 was evaluated in normal as well as medically ovariectomized (Ovx) female cynomolgus monkeys. Serum levels of the C- and N-terminal telopeptides of
Type I collagen (CTx and NTx, respectively) and urinary levels of NTx were monitored as
biomarkers of
bone resorption. Administration of
SB-462795 to medically ovariectomized or normal monkeys resulted in an acute reduction in both serum and urinary markers of
bone resorption within 1.5 h after dosing, and this effect lasted up to 48 h depending on the dose administered. Our data indicate that
SB-462795 potently inhibits human
cathepsin K in osteoclasts, resulting in a rapid inhibition of
bone resorption both in vitro and in vivo in the monkey. These studies also demonstrate the therapeutic potential of
relacatib in the treatment of
postmenopausal osteoporosis and serves to model the planned clinical trials in human subjects.