title: Effects of ONO-5334, a novel orally-active inhibitor of cathepsin K, on bone metabolism.
abstract: In the present study, we examined the in vitro and in vivo pharmacological effects of ONO-5334, a novel inhibitor of cathepsin K, on bone metabolism. In vitro experiments indicated that ONO-5334 is a potent inhibitor of cathepsin K with Ki value of 0.1 nM. Although this compound inhibited other cysteine proteases, such as cathepsin S, L and B, its inhibitory activity for these enzymes was 8 to 320 fold lower than that for cathepsin K. ONO-5334 also inhibited human osteoclasts bone resorption in vitro at a concentration more than 100 fold lower than that of alendronate, a bisphosphonate. While alendronate disrupted actin ring and induced pyknotic nuclei in osteoclasts, ONO-5334 did not have such effects, suggesting that this compound does not affect osteoclasts viability. In in vivo experiments, oral administration of ONO-5334 dose-dependently reduced plasma calcium level increased by parathyroid hormone related peptide in thyroparathyroidectomized rats. Furthermore, in vivo experiment using normal monkeys demonstrated that ONO-5334 decreases serum and urine C-telopeptide of type I collagen level, a bone resorption marker, soon after oral dosing. These levels were consistently decreased below pre-dose levels by repeated oral dosing with ONO-5334 for 7 days. ONO-5334 on the other hand did not affect bone formation markers, serum osteocalcin and bone specific alkaline phosphatase. These findings indicate that ONO-5334 is a specific inhibitor for cathepsin K and thus may be a novel therapeutic agent for metabolic bone diseases.
authors: Discovery Research Laboratories, Ono Pharmaceutical Co., Ltd., Osaka, Japan.
authors: Yasuo
authors: Y
authors: Ochi
authors: Hiroyuki
authors: H
authors: Yamada
authors: Hiroshi
authors: H
authors: Mori
authors: Yasutomo
authors: Y
authors: Nakanishi
authors: Satoshi
authors: S
authors: Nishikawa
authors: Ryoji
authors: R
authors: Kayasuga
authors: Naoki
authors: N
authors: Kawada
authors: Akiko
authors: A
authors: Kunishige
authors: Yasuaki
authors: Y
authors: Hashimoto
authors: Makoto
authors: M
authors: Tanaka
authors: Masafumi
authors: M
authors: Sugitani
authors: Kazuhito
authors: K
authors: Kawabata
mesh_terms: D000199:Actins / Q000378:metabolism; D000284:Administration, Oral; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D016723:Bone Remodeling / Q000187:drug effects; D001862:Bone Resorption / Q000097:blood / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology; D001842:Bone and Bones / Q000187:drug effects* / Q000378:metabolism*; D002118:Calcium / Q000097:blood; D056657:Cathepsin K / Q000037:antagonists & inhibitors* / Q000378:metabolism; D024042:Collagen Type I / Q000097:blood; D005260:Female; D000882:Haplorhini; D006801:Humans; D008297:Male; D010012:Osteogenesis / Q000187:drug effects; D016105:Parathyroidectomy; D010455:Peptides / Q000097:blood; D011480:Protease Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D051381:Rats; D053778:Thiazolidines / Q000008:administration & dosage / Q000494:pharmacology*
chemical_list: D000199:Actins; D015415:Biomarkers; D024042:Collagen Type I; C560865:ONO-5334; D010455:Peptides; D011480:Protease Inhibitors; D053778:Thiazolidines; C052929:collagen type I trimeric cross-linked peptide; D056657:Cathepsin K; D002118:Calcium