title: Effect of SI-591, a new class of cathepsin K inhibitor with peptidomimetic structure, on bone metabolism in vitro and in vivo.
abstract: 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.
authors: Pharmacology Department, Central Research Laboratories, R&D Division, SEIKAGAKU CORPORATION, 1253, Tateno 3-chome, Higashiyamato-shi, Tokyo 207-0021, Japan. Electronic address: toshiaki.fujii@seikagaku.co.jp.
authors: Toshiaki
authors: T
authors: Fujii
authors: Pharmacology Department, Central Research Laboratories, R&D Division, SEIKAGAKU CORPORATION, 1253, Tateno 3-chome, Higashiyamato-shi, Tokyo 207-0021, Japan.
authors: Mizuho
authors: M
authors: Ishikawa
authors: Pharmacology Department, Central Research Laboratories, R&D Division, SEIKAGAKU CORPORATION, 1253, Tateno 3-chome, Higashiyamato-shi, Tokyo 207-0021, Japan.
authors: Akiko
authors: A
authors: Kubo
authors: Pharmacology Department, Central Research Laboratories, R&D Division, SEIKAGAKU CORPORATION, 1253, Tateno 3-chome, Higashiyamato-shi, Tokyo 207-0021, Japan.
authors: Yoshitaka
authors: Y
authors: Tanaka
mesh_terms: D000284:Administration, Oral; D000821:Animal Feed; D000818:Animals; D001381:Azepines / Q000494:pharmacology*; D015519:Bone Density; D001862:Bone Resorption; D001842:Bone and Bones / Q000000981:diagnostic imaging / Q000187:drug effects* / Q000378:metabolism; D002118:Calcium / Q000737:chemistry; D056657:Cathepsin K / Q000037:antagonists & inhibitors*; D024042:Collagen Type I / Q000737:chemistry; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D004151:Dipeptides / Q000494:pharmacology*; D005260:Female; D006801:Humans; D008159:Lumbar Vertebrae / Q000000981:diagnostic imaging / Q000187:drug effects; D008297:Male; D010010:Osteoclasts / Q000187:drug effects / Q000378:metabolism; D015663:Osteoporosis, Postmenopausal / Q000188:drug therapy; D010052:Ovariectomy; D010455:Peptides / Q000737:chemistry; D057786:Peptidomimetics / Q000737:chemistry*; D011859:Radiography; D051381:Rats; D011916:Rats, Inbred F344; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D011994:Recombinant Proteins / Q000737:chemistry
chemical_list: D001381:Azepines; D024042:Collagen Type I; D015853:Cysteine Proteinase Inhibitors; D004151:Dipeptides; D010455:Peptides; D057786:Peptidomimetics; D011994:Recombinant Proteins; C000611312:SI-591; C052929:collagen type I trimeric cross-linked peptide; D056657:Cathepsin K; D002118:Calcium
keywords: Bone formation; Bone mineral density; Bone resorption; Cathepsin K; Inhibitor; Osteoporosis