Design and Synthesis of Tri-Ring P3 Benzamide-Containing Aminonitriles as Potent, Selective, Orally Effective Inhibitors of Cathepsin K
| Autor: | Peppi Prasit, James T. Palmer, Robert G. Strickley, M. David Percival, Liang Liu, Dan-Xiong Wang, Rohan Mendonca, Donald B. Kimmel, Leland C. Ii Burrill, Oballa Renata Marcella, Denis Riendeau, Colena Johnson, Tobee Chung, Young Robert N, Mary E. McGrath, John McCarter, Gregg Wesolowski, Michael C. Venuti, Eric B. Springman, Sevgi B. Rodan, Robert M. Rydzewski, James W. Janc, Bryant Clifford M, Z. Walter Yu, Harry Cheung, Eduardo L. Setti, Tian Zong-Qiang, Dana E. Davis, Jean-Pierre Falgueyret, Philip Enriquez, John R. Somoza, Gideon A. Rodan, Shankar Venkatraman |
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| Rok vydání: | 2005 |
| Předmět: |
Models
Molecular Cathepsin K Administration Oral Biological Availability Crystallography X-Ray Bone resorption Structure-Activity Relationship chemistry.chemical_compound In vivo Nitriles Drug Discovery medicine Animals Humans Bone Resorption Benzamide Bone Density Conservation Agents Molecular Structure biology Chemistry Cathepsins Macaca mulatta Rats Resorption Kinetics Thiazoles Mechanism of action Biochemistry Enzyme inhibitor Drug Design Benzamides biology.protein Ovariectomized rat Molecular Medicine Cattle Collagen Rabbits medicine.symptom Biomarkers |
| Zdroj: | Journal of Medicinal Chemistry. 48:7520-7534 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/jm058198r |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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