1NLJ

CRYSTAL STRUCTURE OF THE CYSTEINE PROTEASE HUMAN CATHEPSIN K IN COMPLEX WITH A COVALENT AZEPANONE INHIBITOR

Summary for 1NLJ

• Entry DOI: 10.2210/pdb1nlj/pdb
• Related: 1atk 1au0 1nL6
• Descriptor: CATHEPSIN K, BENZOFURAN-2-CARBOXYLIC ACID {(S)-3-METHYL-1-[3-OXO-1-(PYRIDIN-2-YLSULFONYL)AZEPAN-4-YLCARBAMOYL]BUTYL}AMIDE (2 entities in total)
• Functional Keywords: hydrolase, sulfhydryl proteinase
• Biological source: Homo sapiens (human)
• Cellular location: Lysosome: P43235
• Total number of polymer chains: 2
• Total formula weight: 48100.17

Authors

Smith, W.W.,Janson, C.A.,Zhao, B. (deposition date: 2003-01-07, release date: 2003-01-14, Last modification date: 2024-10-30)

Primary citation

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.
Azepanone-Based Inhibitors of Human and Rat Cathepsin K
J.Med.Chem., 44:1380-1395, 2001

PubMed Abstract: 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 (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.

PubMed: 11311061
DOI: 10.1021/jm000481x

Experimental method

X-RAY DIFFRACTION (2.4 Å)