A potent, selective, and neutral inhibitor of cathepsin K
Odanacatib (MK-0822) is a potent, orally active and selective inhibitor of Cathepsin K with IC50 value of 0.20 nM [1],
Cathepsin K is expressed predominantly in osteoclasts and degrades the collagen matrix componentsofbone. It plays a central role in mediating bone resorption. And the inhibitor of cathepsin K, Odanacatib, is in development for the treatment of osteoporosis. Based on preclinical evidence and available clinical data from dose-ranging phase IIB trials, odanacatib appears to reduce bone resorptionwhile somewhat preserving bone formation in postmenopausal
Women. Currently, Odanacatib is undergoing evaluation for fracture risk reduction in a phase III trial with ＞16000 patients with postmenopausal osteoporosis [2].
参考文献:
[1] S. Aubrey Stoch, Stefan Zajic, Julie A. Stone, Deborah L. Miller, Lucas van Bortel, Kenneth C. Lasseter, Barnali Pramanik, Caroline Cilissen, Qi Liu, Lida Liu, Boyd B. Scott, Deborah Panebianco, Yu Ding, Keith Gottesdiener & John A. Wagner. Odanacatib, a selective cathepsin K inhibitor to treat osteoporosis: safety, tolerability, pharmacokinetics and pharmacodynamics –results from single oral dose studies in healthy volunteers. British Journal of Clinical Pharmacology. 2012, 75, (5): 1240-1254.
[2] Matt S. Anderson, Isaias Noel Gendrano, Chengcheng Liu, Steven Jeffers,
Chantal Mahon, Anish Mehta, Kate Mostoller, Stefan Zajic, Denise Morris, Jessie Lee, and S. Aubrey Stoch. Odanacatib, a selective Cathepsin K inhibitor, demonstrates comparable pharmacodynamics and pharmacokinetics in older men and postmenopausal women. Endocrine Research. 2014, 99(2):552–560.
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Cell experiment: |
To assess cell survival, differentiated osteoclast (OC) at appr 7×104 cells/cm2 are re-seeded on bovine bone slices with or without 100 nM Odanacatib (ODN). Bone slices are fixed on days 2, 4, 6, and 12 with no media changes. Samples are stained for TRAP activity, and OC number. |
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Animal experiment: |
Sixteen, 8-month-old, female Sprague-Dawley (SD) rats (weight, 385?±?55?g) are given water and soft diet food ad libitum in a temperature-controlled environment with regular 12-h cycles of light and dark. The rats are randomised into 4 groups, with 4 rats in each group: sham group, OVX?+?Veh group, OVX?+?ODN-l group and OVX?+?ODN-h group. Following implant insertion, Odanacatib (ODN, 5?mg/mL) is administered to the OVX?+?ODN-l and OVX?+?ODN-h groups at concentrations of 1?mL/kg and 6?mL/kg, respectively, by gavaging once a day for 8 weeks. The OVX?+?Veh group is gavaged with 0.5% sodium carboxymethyl cellulose at a concentration of 6?mL/kg over the same duration. After the gavage administration, the rats of each group are sacrificed by injecting sodium pentobarbital intravenously. The implants are harvested and fixed in 10% buffered formalin together with the surrounding bone. |
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参考文献: [1]. Jacques Yves Gauthier, et al. The discovery of odanacatib (MK-0822), a selective inhibitor of cathepsin K. Bioorg Med Chem Lett. 2008 Feb 1;18(3):923-8. |
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