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.
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.
Kim
M K
MK
Dong-A Research Laboratories, Dong-A Pharmaceutical Co., Ltd., Gyeonggi-do, Republic of Korea.
Kim
H D
HD
Park
J H
JH
Lim
J I
JI
Yang
J S
JS
Kwak
W Y
WY
Sung
S Y
SY
Kim
H J
HJ
Kim
S H
SH
Lee
C H
CH
Shim
J Y
JY
Bae
M H
MH
Shin
Y A
YA
Huh
Y
Y
Han
T D
TD
Chong
W
W
Choi
H
H
Ahn
B N
BN
Yang
S O
SO
Son
M H
MH
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
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