| Autor: |
Palmer, J. T., Bryant, C., Wang, D.-X., Davis, D. E., Setti, E. L., Rydzewski, R. M., Venkatraman, S., Tian, Z.-Q., Burrill, L. C., Mendonca, R. V., Springman, E., McCarter, J., Chung, T., Cheung, H., Janc, J. W., McGrath, M., Somoza, J. R., Enriquez, P., Yu, Z. W., Strickley, R. M., Liu, L., Venuti, M. C., Percival, M. D., Falgueyret, J.-P., Prasit, P., Oballa, R., Riendeau, D., Young, R. N., Wesolowski, G., Rodan, S. B., Johnson, C., Kimmel, D. B., Rodan, G. |
| Zdroj: |
Journal of Medicinal Chemistry; December 2005, Vol. 48 Issue: 24 p7520-7534, 15p |
| Abstrakt: |
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: |
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