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ENDOCRINE AND DIABETES

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

Dong-A Research Laboratories (M.K.K., H.D.K., J.H.P., J.I.L., J.S.Y., W.Y.K., S.Y.S., H.J.K., S.H.K., M.H.S.), Dong-A Pharmaceutical Co., Ltd., Gyeonggi-do, Republic of Korea; Yuhan Research Institute (C.H.L., J.Y.S., M.H.B., Y.A.S., Y.H., T.D.H., W.C., H.C., B.N.A.), Yuhan Corporation, Gyeonggi-do, Republic of Korea; and Department of Radiology (S.O.Y.), Eulji University Hospital, Daejeon, Republic of Korea.

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.

Address correspondence to: Dr. Moon-Ho Son, 47-5, Sanggal-Dong, Giheung-Gu, Yongin-Si, Gyeonggi-Do 446-905, Republic of Korea. E-mail: ssonmh{at}donga.co.kr

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