Identification of a potent and selective non-basic cathepsin K inhibitor

https://doi.org/10.1016/j.bmcl.2005.12.071Get rights and content

Abstract

Based on our previous study with trifluoroethylamine as a P2–P3 amide isostere of cathepsin K inhibitor, further optimization led to identification of compound 22 (L-873724) as a potent and selective non-basic cathepsin K inhibitor. This compound showed excellent pharmacokinetics and efficacy in an ovariectomized (OVX) rhesus monkey model. The volumes of distribution close to unity were consistent with this compound not being lysosomotropic, which is a characteristic of basic cathepsin K inhibitors.

Graphical abstract

Based on our previous study with trifluoroethylamine as a P2–P3 amide isostere of cathepsin K inhibitor, further optimization led to identification of compound 22 (L-873724) as a potent and selective non-basic cathepsin K inhibitor.

  1. Download : Download full-size image

References and notes (15)

  • W.C. Black et al.

    Bioorg. Med. Chem. Lett.

    (2005)
  • J. Robichaud et al.

    J. Med. Chem.

    (2003)
  • J.-P. Falgueyret et al.

    J. Med. Chem.

    (2005)
  • J.T. Palmer et al.

    J. Med. Chem.

    (2005)
  • U.B. Grabowska et al.

    Curr. Opin. Drug Discov. Devel.

    (2005)
    R.W. Marquis

    Annu. Rep. Med. Chem.

    (2004)
There are more references available in the full text version of this article.

Cited by (86)

  • Signalling pathways linking cysteine cathepsins to adverse cardiac remodelling

    2020, Cellular Signalling
    Citation Excerpt :

    On the other hand, cathepsin K inhibitors have shown significant promise in phase I-III clinical trials for treating osteoporosis and osteoarthritis. The cathepsin K inhibitor, L-873724 (Merck), is a non-lysosomotropic, potent and selective (>800-fold over other cathepsins) inhibitor, that was shown to suppress bone resorption in rabbit and rhesus monkey [173]. Due to the short half-life and clearance (Cl = 7.5 mL/min/kg) of.

  • Complexity of cancer protease biology: Cathepsin K expression and function in cancer progression

    2015, Seminars in Cancer Biology
    Citation Excerpt :

    Once protonated within the subcellular acidic organelles, the inhibitors are entrapped in endosomes and lysosomes [182,183], where their accumulation may result in off-target inhibition of cysteine proteases other than CatK. Therefore, the strategy shifted towards the design of non-basic inhibitors, which still maintain their potency and selectivity against individual cathepsins, and show their efficacy in cell-based assays thus being the most safe for applications [184,185]. There are currently over 1800 CatK inhibitors indexed in the Binding Database (available online at http://www.bindingdb.org) and more than 50 patent applications for small-molecule CatK inhibitors have been filed in the past decade [42,186].

  • Steering the osteoclast through the demineralization-collagenolysis balance

    2013, Bone
    Citation Excerpt :

    In contrast, mild inhibition of carbonic anhydrase should allow collagenolysis to proceed as fast as demineralization, thereby ensuring continuation of the local resorption event, thus promoting the formation of trenches at the expense of round pits. The following inhibitors of OC resorption were used: 6-ethoxyzolamide (Sigma-Aldrich, Broendby, Denmark), specific inhibitor of carbonic anhydrase, 20 mM stock in DMSO, stored at − 20 °C; E64 (Sigma-Aldrich), cysteine-protease inhibitor, 1 mM stock in H2O, stored at − 20 °C; L873724, an inhibitor specific of CatK [20,22,23] (a generous gift from MSD, Rahway, USA), 10 mM stock in DMSO (Sigma-Aldrich) stored at − 20 °C. Human CD14+ cells were isolated from buffy coats of healthy volunteers (approved by the local ethics committee, 2007-0019) and differentiated into multinucleated OCs through the use of 25 ng/ml M-CSF and 25 ng/ml RANKL (R&D, Abingdon, England, UK) as described previously [17].

View all citing articles on Scopus
View full text