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Hoffmann, R. A wiki for the life sciences where authorship matters. Nature Genetics (2008)

Azepanone-based inhibitors of human and rat cathepsin K.

The synthesis, in vitro activities, and pharmacokinetics of a series of azepanone-based inhibitors of the cysteine protease cathepsin K (EC 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 (K(i) = 0.16 nM) as well as 24, a potent inhibitor of both human (K(i) = 0.0048 nM) and rat (K(i,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.[1]


  1. Azepanone-based inhibitors of human and rat cathepsin K. 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.M., James, I.E., Gress, C.J., Bradley, B.R., Lark, M.W., Gowen, M., Veber, D.F. J. Med. Chem. (2001) [Pubmed]
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