| Autor: |
Marquis, R. W., Ru, Y., Zeng, J., Trout, R. E. L., LoCastro, S. M., Gribble, A. D., Witherington, J., Fenwick, A. E., Garnier, B., Tomaszek, T., Tew, D., Hemling, M. E., Quinn, C. J., Smith, W. W., Zhao, B., McQueney, M. S., Janson, C. A., D'Alessio, K., Veber, D. F. |
| Zdroj: |
Journal of Medicinal Chemistry; March 2001, Vol. 44 Issue: 5 p725-736, 12p |
| Abstrakt: |
Cathepsin K (EC 3.4.22.38), a cysteine protease of the papain superfamily, is predominantly expressed in osteoclasts and has been postulated as a target for the treatment of osteoporosis. Crystallographic and structure−activity studies on a series of acyclic ketone-based inhibitors of cathepsin K have led to the design and identification of two series of cyclic ketone inhibitors. The mode of binding for four of these cyclic and acyclic inhibitors to cathepsin K is discussed and compared. All of the structures are consistent with addition of the active site thiol to the ketone of the inhibitors with the formation of a hemithioketal. Cocrystallization of the C-3 diastereomeric 3-amidotetrahydrofuran-4-one analogue 16 with cathepsin K showed the inhibitor to occupy the unprimed side of the active site with the 3S diastereomer preferred. This C-3 stereochemical preference is in contrast to the X-ray cocrystal structures of the 3-amidopyrrolidin-4-one inhibitors 29 and 33 which show these inhibitors to prefer binding of the 3R diastereomer. The 3-amidopyrrolidin-4-one inhibitors were bound in the active site of the enzyme in two alternate directions. Epimerization issues associated with the labile α-amino ketone diastereomeric center contained within these inhibitor classes has proven to limit their utility despite promising pharmacokinetics displayed in both series of compounds. |
| Databáze: |
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