SI-591[N-[1-[[[(1S)-3-[[(3S)-hexahydro-2-oxo-1H-azepin-3-yl]amino]-1-(1-methylethyl)-2,3-dioxopropyl]amino]carbonyl]cyclohexyl]-2-furancarboxamide] is an orally bioavailable compound that was synthesized as one of several unique
peptidomimetic compounds without a basic group. This compound was found to have the ability to inhibit
cathepsin K, a lysosomal
cysteine protease.
Cathepsin K is known to be expressed in osteoclasts and involved in bone loss processes. In this study,
SI-591 was shown to inhibit the activity of various purified
cathepsin molecules at nanomolar concentrations but had high selectivity for
cathepsin K over other subtypes including B and L.
SI-591 also decreased the level of CTX-I, a
bone resorption marker, which was released from osteoclasts in vitro in a dose-dependent manner. The mobilization of
calcium from the bones to the blood stream is known to increase in rats fed with a low
calcium diet;
SI-591 inhibited this increase in serum
calcium level at an oral dose of 3mg/kg. Furthermore,
SI-591 significantly decreased the level of CTX-I and DPD,
bone resorption markers, at oral doses of 10mg/kg or less in ovariectomized rats, while it did not affect the level of BGP, a bone formation marker. In addition,
SI-591 prevented bone mineral density loss in the lumber vertebrae and femurs in ovariectomized rats. These results suggest that
SI-591 inhibits
bone resorption without affecting osteoblast maturation. Therefore,
SI-591, a novel
cathepsin K inhibitor, could be a promising agent for the treatment of
postmenopausal osteoporosis.