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Le T Duong, Albert T Leung, Bente Langdahl
Cathepsin K (CatK), a cysteine protease, is highly expressed by osteoclasts and very efficiently degrades type I collagen, the major component of the organic bone matrix. Robust genetic and pharmacological preclinical studies consistently demonstrate that CatK inhibition increases bone mass, improves bone microarchitecture and strength. Recent advances in the understanding of the molecular and cellular mechanisms involved in bone modeling and remodeling suggest that inhibition of CatK decreases bone resorption, but increases the number of cells of osteoclast lineage...
April 2016: Calcified Tissue International
Marion Gamsjäger, Heinrich Resch
Cathepsin K, a cysteine protease, is an essential enzyme in degradation of collagen type I. Since cathepsin K is relatively specific to osteoclasts, it represents a promising candidate for drug development. In the past decades, efforts have been made in developing highly potent, selective and orally applicable cathepsin K inhibitors. In contrast to balicatib and relacatib, whose drug development programmes were stopped due to cutaneous side-effects related to limited drug specificity, the more specific cathepsin K inhibitors odanacatib (ODN) and ONO-5334 have entered clinical trials...
February 2015: Wiener Medizinische Wochenschrift
G B Stroup, S Kumar, C P Jerome
The cysteine protease cathepsin K is involved in osteoclast-mediated bone resorption. We evaluated the effect of daily oral dosing of an inhibitor of human cathepsin K (SB-462795 [relacatib]) for 9 months on bone turnover, mass, and architecture in estrogen-deficient cynomolgus monkeys. Ovariectomized animals were treated orally with relacatib at 1, 3, or 10 mg/kg/day, or oral vehicle plus alendronate at 0.05 mg/kg by IV injection once every 2 weeks. The control groups, ovariectomized and sham-ovariectomized animals, received vehicle (all groups n = 20 animals)...
October 2009: Calcified Tissue International
Jacques Yves Gauthier, Nathalie Chauret, Wanda Cromlish, Sylvie Desmarais, Le T Duong, Jean-Pierre Falgueyret, Donald B Kimmel, Sonia Lamontagne, Serge Léger, Tammy LeRiche, Chun Sing Li, Frédéric Massé, Daniel J McKay, Deborah A Nicoll-Griffith, Renata M Oballa, James T Palmer, M David Percival, Denis Riendeau, Joel Robichaud, Gideon A Rodan, Sevgi B Rodan, Carmai Seto, Michel Thérien, Vouy-Linh Truong, Michael C Venuti, Gregg Wesolowski, Robert N Young, Robert Zamboni, W Cameron Black
Odanacatib is a potent, selective, and neutral cathepsin K inhibitor which was developed to address the metabolic liabilities of the Cat K inhibitor L-873724. Substituting P1 and modifying the P2 side chain led to a metabolically robust inhibitor with a long half-life in preclinical species. Odanacatib was more selective in whole cell assays than the published Cat K inhibitors balicatib and relacatib. Evaluation in dermal fibroblast culture showed minimal intracellular collagen accumulation relative to less selective Cat K inhibitors...
February 1, 2008: Bioorganic & Medicinal Chemistry Letters
S Kumar, L Dare, J A Vasko-Moser, I E James, S M Blake, D J Rickard, S-M Hwang, T Tomaszek, D S Yamashita, R W Marquis, H Oh, J U Jeong, D F Veber, M Gowen, M W Lark, G Stroup
Cathepsin K is an osteoclast-derived cysteine protease that has been implicated as playing a major role in bone resorption. A substantial body of evidence indicates that cathepsin K is critical in osteoclast-mediated bone resorption and suggests that its pharmacological inhibition should result in inhibition of bone resorption in vivo. Here we report the pharmacological characterization of SB-462795 (relacatib) as a potent and orally bioavailable small molecule inhibitor of cathepsin K that inhibits bone resorption both in vitro in human tissue and in vivo in cynomolgus monkeys...
January 2007: Bone
Dennis S Yamashita, Robert W Marquis, Ren Xie, Sirishkumar D Nidamarthy, Hye-Ja Oh, Jae U Jeong, Karl F Erhard, Keith W Ward, Theresa J Roethke, Brian R Smith, H-Y Cheng, Xiaoliu Geng, Fan Lin, Priscilla H Offen, Bing Wang, Neysa Nevins, Martha S Head, R Curtis Haltiwanger, Amy A Narducci Sarjeant, Louise M Liable-Sands, Baoguang Zhao, Ward W Smith, Cheryl A Janson, Enoch Gao, Thaddeus Tomaszek, Michael McQueney, Ian E James, Catherine J Gress, Denise L Zembryki, Michael W Lark, Daniel F Veber
The syntheses, in vitro characterizations, and rat and monkey in vivo pharmacokinetic profiles of a series of 5-, 6-, and 7-methyl-substituted azepanone-based cathepsin K inhibitors are described. Depending on the particular regiochemical substitution and stereochemical configuration, methyl-substituted azepanones were identified that had widely varied cathepsin K inhibitory potency as well as pharmacokinetic properties compared to the 4S-parent azepanone analogue, 1 (human cathepsin K, K(i,app) = 0.16 nM, rat oral bioavailability = 42%, rat in vivo clearance = 49...
March 9, 2006: Journal of Medicinal Chemistry
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