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

摘要

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 os-teoclasts 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 IC_(50) values of 11 and 427 nM,respectively.OST-4077 suppressed bone resorption induced by rabbit oste-oclasts (IC_(50),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 (ED_(50),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.