title: An orally active cathepsin K inhibitor, furan-2-carboxylic acid, 1-{1-[4-fluoro-2-(2-oxo-pyrrolidin-1-yl)-phenyl]-3-oxo-piperidin-4-ylcarbamoyl}-cyclohexyl)-amide (OST-4077), inhibits osteoclast activity in vitro and bone loss in ovariectomized rats.
abstract: Human cathepsin K, a cysteine proteinase of the papain family, has been recognized as a potential drug target for the treatment of osteoporosis. The predominant expression of cathepsin K in osteoclasts has rendered the enzyme into a major target for the development of novel antiresorptive drugs. Now, we report the pharmacological properties of OST-4077 [furan-2-carboxylic acid (1-{1-[4-fluoro-2-(2-oxo-pyrrolidin-1-yl)-phenyl]-3-oxo-piperidin-4-ylcarbamoyl}-cyclohexyl)-amide] as a novel selective cathepsin K inhibitor. Human and rat cathepsin K were inhibited in vitro by OST-4077 with the IC50 values of 11 and 427 nM, respectively. OST-4077 suppressed bone resorption induced by rabbit osteoclasts (IC50, 37 nM) but did not affect bone mineralization or cellular alkaline phosphatase activity in MC3T3-E1 cells. Parathyroid hormone-induced bone resorption was inhibited in a dose-dependent manner in thyroparathyroidectomized rats gavaged with a single dose of OST-4077 (ED50, 69 mg/kg). When given orally twice daily for 4 weeks to 3-month-old ovariectomized (OVX) rats, OST-4077 dose-dependently prevented bone loss, as monitored by bone densitometry, ash content, and urinary excretion of deoxypyridinoline. No change in serum osteocalcin in the OVX rats by OST-4077 suggested that bone formation might not be affected by the agent. In summary, OST-4077 selectively inhibited bone resorbing activities of osteoclasts and prevented bone loss induced by estrogen deficiency but did not affect bone formation. OST-4077, an orally active selective human cathepsin K inhibitor, may have the therapeutic potential for the treatment of diseases characterized by excessive bone loss including osteoporosis.
authors.affiliation: Dong-A Research Laboratories, Dong-A Pharmaceutical Co., Ltd., Gyeonggi-do, Republic of Korea.
authors.forename: M K
authors.initials: MK
authors.lastname: Kim
authors.forename: H D
authors.initials: HD
authors.lastname: Kim
authors.forename: J H
authors.initials: JH
authors.lastname: Park
authors.forename: J I
authors.initials: JI
authors.lastname: Lim
authors.forename: J S
authors.initials: JS
authors.lastname: Yang
authors.forename: W Y
authors.initials: WY
authors.lastname: Kwak
authors.forename: S Y
authors.initials: SY
authors.lastname: Sung
authors.forename: H J
authors.initials: HJ
authors.lastname: Kim
authors.forename: S H
authors.initials: SH
authors.lastname: Kim
authors.forename: C H
authors.initials: CH
authors.lastname: Lee
authors.forename: J Y
authors.initials: JY
authors.lastname: Shim
authors.forename: M H
authors.initials: MH
authors.lastname: Bae
authors.forename: Y A
authors.initials: YA
authors.lastname: Shin
authors.forename: Y
authors.initials: Y
authors.lastname: Huh
authors.forename: T D
authors.initials: TD
authors.lastname: Han
authors.forename: W
authors.initials: W
authors.lastname: Chong
authors.forename: H
authors.initials: H
authors.lastname: Choi
authors.forename: B N
authors.initials: BN
authors.lastname: Ahn
authors.forename: S O
authors.initials: SO
authors.lastname: Yang
authors.forename: M H
authors.initials: MH
authors.lastname: Son
mesh_terms: D000469:Alkaline Phosphatase / Q000378:metabolism; D000577:Amides / Q000494:pharmacology* / Q000627:therapeutic use*; D000818:Animals; D015415:Biomarkers; D015519:Bone Density / Q000187:drug effects; D050071:Bone Density Conservation Agents / Q000494:pharmacology* / Q000627:therapeutic use*; D001862:Bone Resorption / Q000188:drug therapy* / Q000378:metabolism; D056657:Cathepsin K; D002403:Cathepsins / Q000037:antagonists & inhibitors* / Q000235:genetics; D003001:Cloning, Molecular; D004791:Enzyme Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use*; D004967:Estrogens / Q000172:deficiency; D005260:Female; D005663:Furans / Q000494:pharmacology* / Q000627:therapeutic use*; D006801:Humans; D010010:Osteoclasts / Q000187:drug effects*; D010052:Ovariectomy; D010281:Parathyroid Hormone / Q000494:pharmacology; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: C512989:1-(1-(4-fluoro-2-(2-oxopyrrolidin-1-yl)phenyl)-3-oxopiperidin-4-ylcarbamoyl)cyclohexyl furan-2-carboxylic acid amide; D000577:Amides; D015415:Biomarkers; D050071:Bone Density Conservation Agents; D004791:Enzyme Inhibitors; D004967:Estrogens; D005663:Furans; D010281:Parathyroid Hormone; D000469:Alkaline Phosphatase; D002403:Cathepsins; C534130:CTSK protein, human; D056657:Cathepsin K; C534133:Ctsk protein, rat