Online citations, reference lists, and bibliographies.
← Back to Search

Azepanone-based Inhibitors Of Human And Rat Cathepsin K.

R. W. Marquis, Y. Ru, S. LoCastro, J. Zeng, D. Yamashita, H. J. Oh, K. Erhard, L. D. Davis, T. Tomaszek, D. Tew, K. Salyers, J. Proksch, K. Ward, B. Smith, M. Levy, M. D. Cummings, R. C. Haltiwanger, G. Trescher, B. Wang, M. Hemling, C. J. Quinn, H. Cheng, F. Lin, W. Smith, C. Janson, B. Zhao, M. Mcqueney, K. D'alessio, C. Lee, A. Marzulli, R. A. Dodds, S. Blake, S. Hwang, I. E. James, C. Gress, B. Bradley, M. Lark, M. Gowen, D. Veber
Published 2001 · Medicine, Chemistry

Cite This
Download PDF
Analyze on Scholarcy
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.

This paper is referenced by
Parallel solution-phase synthesis of mechanism-based cysteine protease inhibitors.
A. Lee (2001)
Future of anticathepsin K drugs: dual therapy for skeletal disease and atherosclerosis?
I. Podgorski (2009)
Advances in the discovery of cathepsin K inhibitors on bone resorption
J. Lu (2018)
Potent and selective cathepsin K inhibitors.
Tsuyoshi Shinozuka (2006)
Synthesis and evaluation of cis-hexahydropyrrolo[3,2-b]pyrrol-3-one peptidomimetic inhibitors of CAC1 cysteinyl proteinases.
M. Quibell (2005)
Benzodioxocin-3-ones and N-acyl-3-amino-3-buten-2-ones: novel classes of cathepsin K cysteine protease inhibitors.
D. Yamashita (2004)
Asymmetric synthesis of a potent azepanone-based inhibitor of the cysteine protease cathepsin K
R. Trout (2005)
Assessment of Hydration Thermodynamics at Protein Interfaces with Grid Cell Theory.
Georgios Gerogiokas (2016)
Combinatorial Strategies for Targeting Protein Families: Application to the Proteases
D. Maly (2002)
Novel therapeutic targets in osteoporosis
J. Tobias (2002)
Substrate mapping and inhibitor profiling of falcipain-2, falcipain-3 and berghepain-2: implications for peptidase anti-malarial drug discovery.
M. Ramjee (2006)
A structural screening approach to ketoamide-based inhibitors of cathepsin K.
D. G. Barrett (2005)
The Future of Cysteine Cathepsins in Disease Management.
Lovro Kramer (2017)
Murine and human cathepsin B exhibit similar properties: possible implications for drug discovery
Dejan Caglič (2009)
3-Acylamino-azetidin-2-one as a novel class of cysteine proteases inhibitors.
N. Zhou (2003)
Peptidomimetic 2-cyanopyrrolidines as potent selective cathepsin L inhibitors
M. R. Yadav (2008)
Collagenolytic Activities of the Major Secreted Cathepsin L Peptidases Involved in the Virulence of the Helminth Pathogen, Fasciola hepatica
M. Robinson (2011)
Synthesis of 3-oxooxa- and 3-oxoazacycloalk-4-enes by ring-closing metathesis. Application to the synthesis of an inhibitor of cathepsin K
C. Taillier (2007)
Identification of novel cathepsin K inhibitors using ligand-based virtual screening and structure-based docking
Yali Wang (2016)
A highly potent inhibitor of cathepsin K (relacatib) reduces biomarkers of bone resorption both in vitro and in an acute model of elevated bone turnover in vivo in monkeys.
S. Kumar (2007)
Optimization of peptidyl allyl sulfones as clan CA cysteine protease inhibitors
B. D. Fennell (2013)
Ligand preorganization may be accompanied by entropic penalties in protein-ligand interactions.
A. P. Benfield (2006)
Inhibition of Prostate Cancer Skeletal Metastases by Targeting Cathepsin K
J. Zhang (2010)
4-Aminophenoxyacetic acids as a novel class of reversible cathepsin K inhibitors.
Tsuyoshi Shinozuka (2006)
1,2,4-thiadiazole: a novel Cathepsin B inhibitor.
Regis Leung-Toung (2003)
Cysteine protease inhibitors as potential antiparasitic agents
Joon-Yong Chung (2005)
Synthesis and evaluation of conformationally constrained peptide replacements and studies toward the total synthesis of kidamycin
H. Plake (2004)
Cathepsin S inhibitors
V. Leroy (2004)
General solid-phase method to prepare novel cyclic ketone inhibitors of the cysteine protease cruzain.
L. Huang (2002)
How to Test Osteoporosis Treatments in Experimental Animals
Rob van 't Hof (2011)
Rat cathepsin K: Enzymatic specificity and regulation of its collagenolytic activity.
F. Lecaille (2019)
Keto-1,3,4-oxadiazoles as cathepsin K inhibitors.
J. Palmer (2006)
See more
Semantic Scholar Logo Some data provided by SemanticScholar