生物活性

• 描述Cathepsin K (Cat K) is a lysosomal cysteine protease that is responsible for osteoclastic bone resorption. Odanacatib is a selective and reversible inhibitor of both human and rabbit Cat K with IC₅₀ values of 0.2 nM and 1.0 nM, respectively^[1]. Odanacatib reduced the release of collagen type I C-telopeptide of (CTx) at a dose-dependent manner with IC₅₀ of 9.4 ± 1.0 nM in human osteoclasts. When treated with more than 10 nM odanacatib for 5 days, osteoclasts showed smaller discontinuous trails of resorption puts compared to untreated cells. Odanacatib up to 100 nM suppressed the accumulation of resorption surfacein osteoclasts 5 days after the treatment. The efficacy of odanacatib in reducing resorption area per multinucleated TRAP⁺ cell was determined with an IC₅₀ value of 6.5 ± 3.5 nM. In mature osteoclasts plated on bone surface, 4-day treatment of 100 nM odanacatib stimulated the retention of intracellular vesicles and the expressions of Cat K and TRAP. Also, cells treated with odanacatib at the same condition showed dramatically accumulated numbers of bone matrix-contining vesicles compared to untreated controls^[2]. In a study of 7- to 8-week-old male wild-type BALB/cJ mice with bacterial infection, the bone resorption in the periapical lesion areas was significantly reduced in the group with odanacatib (3.606 mg/kg/week) at 42 days. The number of osteoclasts and the mRNA level of Cat K were decreased in the infected mice with odanacatib (3.606 mg/kg/week) compared to the ones without treatment^[3].
• 作用机制Odanacatib inhibits Cat K by directly binding with Cys25 side chain of Cat K with a covalent bond^[4].

• 动物研究
  剂量	Monkey: 6 mg/kg, 30 mg/kg[5] (p.o., q.d.) Rat: 5 mg/kg, 30 mg/kg[6] (p.o.)
  给药途径	p.o.

• 临床研究

• NCT号	适应症或疾病	临床期	招募状态	预计完成时间	地点
  NCT00242476	Vitamin D Deficiency	Phase 2	Completed	-	-
  NCT00397683	Osteoarthritis	Phase 2	Terminated	-	United States, California ... more >> Call for Information Palm Desert, California, United States, 92260 Call for Information Pomona, California, United States, 91767 Call for Information Torrance, California, United States, 90505 Call for Information Upland, California, United States, 91786 United States, Florida Call for Information Coral Gables, Florida, United States, 33134 Call for Information Hialeah, Florida, United States, 33010 Call for Information South Miami, Florida, United States, 33143-0000 United States, New York Call for Information Rochester, New York, United States, 14168 Call for Information Rochester, New York, United States, 14609 Call for Information Rochester, New York, United States, 14618 United States, Pennsylvania Call for Information Norristown, Pennsylvania, United States, 19401 Call for Information Perkasie, Pennsylvania, United States, 18944 Chile Merck Sharp & Dohme (I.A.) Corp. Santiago, Chile, 6761641 Colombia Frosst Laboratories Inc. Bogota, Cundinamarca, Colombia Mexico Merck Sharp & Dohme De Mexico, S.A. De C.V. Mexico, D.f., Mexico, 1090 Poland MSD Polska Sp. z o.o. Dzial Medyczny Warszawa, Poland, 00-867 Collapse <<
  NCT00112437	Osteoporosis	Phase 2	Completed	-	-

• 更多
• 参考文献

• [1] Gauthier JY, Chauret N, et al. The discovery of odanacatib (MK-0822), a selective inhibitor of cathepsin K. Bioorg Med Chem Lett. 2008;18(3):923-8.

  [2] Leung P, Pickarski M, et al. The effects of the cathepsin K inhibitor odanacatib on osteoclastic bone resorption and vesicular trafficking. Bone. 2011 Oct;49(4):623-35.

  [3] Hao L, Chen W, et al. A small molecule, odanacatib, inhibits inflammation and bone loss caused by endodontic disease. Infect Immun. 2015;83(4):1235-45.

  [4] Lu J, Wang M, et al. Advances in the discovery of cathepsin K inhibitors on bone resorption. J Enzyme Inhib Med Chem. 2018;33(1):890-904.