Design and synthesis of tri-ring P3 benzamide-containing aminonitriles as potent, selective, orally effective inhibitors of cathepsin K |
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Authors: | Palmer James T Bryant Clifford Wang Dan-Xiong Davis Dana E Setti Eduardo L Rydzewski Robert M Venkatraman Shankar Tian Zong-Qiang Burrill Leland C Mendonca Rohan V Springman Eric McCarter John Chung Tobee Cheung Harry Janc James W McGrath Mary Somoza John R Enriquez Philip Yu Z Walter Strickley Robert M Liu Liang Venuti Michael C Percival M David Falgueyret Jean-Pierre Prasit Peppi Oballa Renata Riendeau Denis Young Robert N Wesolowski Gregg Rodan Sevgi B Johnson Colena Kimmel Donald B Rodan Gideon |
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Institution: | Celera Genomics, Inc., 180 Kimball Way, South San Francisco, California 94080, USA. jim.palmer@celera.com |
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Abstract: | We have prepared a series of achiral aminoacetonitriles, bearing tri-ring benzamide moieties and an aminocyclohexanecarboxylate residue at P2. This combination of binding elements resulted in sub-250 pM, reversible, selective, and orally bioavailable cathepsin K inhibitors. Lead compounds displayed single digit nanomolar inhibition in vitro (of rabbit osteoclast-mediated degradation of bovine bone). The best compound in this series, 39n (CRA-013783/L-006235), was orally bioavailable in rats, with a terminal half-life of over 3 h. 39n was dosed orally in ovariectomized rhesus monkeys once per day for 7 days. Collagen breakdown products were reduced by up to 76% dose-dependently. Plasma concentrations of 39n above the bone resorption IC50 after 24 h indicated a correlation between functional cellular and in vivo assays. Inhibition of collagen breakdown by cathepsin K inhibitors suggests this mechanism of action may be useful in osteoporosis and other indications involving bone resorption. |
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