| Autor: |
Marquis, R. W., Ru, Y., LoCastro, S. M., Zeng, J., Yamashita, D. S., Oh, H.-J., Erhard, K. F., Davis, L. D., Tomaszek, T. A., Tew, D., Salyers, K., Proksch, J., Ward, K., Smith, B., Levy, M., Cummings, M. D., Haltiwanger, R. C., Trescher, G., Wang, B., Hemling, M. E., Quinn, C. J., Cheng, H-Y., Lin, F., Smith, W. W., Janson, C. A., Zhao, B., McQueney, M. S., D'Alessio, K., Lee, C.-P., Marzulli, A., Dodds, R. A., Blake, S., Hwang, S.-H., James, I. E., Gress, C. J., Bradley, B. R., Lark, M. W., Gowen, M., Veber, D. F. |
| Zdroj: |
Journal of Medicinal Chemistry; April 2001, Vol. 44 Issue: 9 p1380-1395, 16p |
| Abstrakt: |
The synthesis, in vitro activities, and pharmacokinetics of a series of azepanone-based inhibitors of the cysteine protease cathepsin K (EC 3.4.22.38) are described. These compounds show improved configurational stability of the C-4 diastereomeric center relative to the previously published five- and six-membered ring ketone-based inhibitor series. Studies in this series have led to the identification of 20, a potent, selective inhibitor of human cathepsin K (Ki = 0.16 nM) as well as 24, a potent inhibitor of both human (Ki = 0.0048 nM) and rat (Ki,app = 4.8 nM) cathepsin K. Small-molecule X-ray crystallographic analysis of 20 established the C-4 S stereochemistry as being critical for potent inhibition and that unbound 20 adopted the expected equatorial conformation for the C-4 substituent. Molecular modeling studies predicted the higher energy axial orientation at C-4 of 20 when bound within the active site of cathepsin K, a feature subsequently confirmed by X-ray crystallography. Pharmacokinetic studies in the rat show 20 to be 42% orally bioavailable. Comparison of the transport of the cyclic and acyclic analogues through CaCo-2 cells suggests that oral bioavailability of the acyclic derivatives is limited by a P-glycoprotein-mediated efflux mechanism. It is concluded that the introduction of a conformational constraint has served the dual purpose of increasing inhibitor potency by locking in a bioactive conformation as well as locking out available conformations which may serve as substrates for enzyme systems that limit oral bioavailability. |
| Databáze: |
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