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Molecular Pharmacology

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Research ArticleArticle

Effect of Cathepsin K Inhibitor Basicity on in Vivo Off-Target Activities

Sylvie Desmarais, W. Cameron Black, Renata Oballa, Sonia Lamontagne, Denis Riendeau, Paul Tawa, Le Thi Duong, Maureen Pickarski and M. David Percival
Molecular Pharmacology January 2008, 73 (1) 147-156; DOI: https://doi.org/10.1124/mol.107.039511
Sylvie Desmarais
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W. Cameron Black
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Renata Oballa
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Sonia Lamontagne
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Denis Riendeau
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Paul Tawa
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Le Thi Duong
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Maureen Pickarski
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M. David Percival
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Abstract

Cathepsin K is a lysosomal cysteine protease that is a pharmacological target for the treatment of osteoporosis. Previous studies showed that basic, lipophilic cathepsin K inhibitors are lysosomotropic and have greater activities in cell-based assays against cathepsin K, as well as the physiologically important lysosomal cysteine cathepsins B, L, and S, than expected based on their potencies against these isolated enzymes. Long-term administration of the basic cathepsin K inhibitors N-(1-(((cyanomethyl)amino)carbonyl)cyclohexyl)-4-(2-(4-methyl-piperazin-1-yl)-1,3-thiazol-4-yl)benzamide (L-006235) and balicatib to rats at a supratherapeutic dose of 500 mg/kg/day for 4 weeks resulted in increased tissue protein levels of cathepsin B and L but had no effect on cathepsin B and L message. This is attributed to the inhibitor engagement of these off-target enzymes and their stabilization to proteolytic degradation. No such increase in these tissue cathepsins was detected at the same dose of N-(cyanomethyl)-N2-{(1S)-2,2,2-trifluoro-1-[4'-methylsulfonyl)biphenyl-4-yl]ethyl}-l-leucinamide (L-873724), a potent nonbasic cathepsin K inhibitor with a similar off-target profile, although all three inhibitors provided similar plasma exposures. Using an activity-based probe, 125I-BIL-DMK, in vivo inhibition of cathepsins B, L, and S was detected in tissues of mice given a single oral dose of L-006235 and balicatib, but not in mice given L-873724. In each case, similar tissue levels were achieved by all three compounds, thereby demonstrating the in vivo cathepsin selectivity of L-873724. In conclusion, basic cathepsin K inhibitors demonstrate increased off-target cysteine cathepsin activities than their nonbasic analogs and potentially have a greater risk of adverse effects associated with inhibition of these cathepsins.

Footnotes

  • ABBREVIATIONS: Cat, cathepsin; BIL-DMK, biphenyl-leucine-diazomethylketone; E-64, trans-epoxysuccinyl-L-leucylamido(4-guanidino)butane; Ca-074, N-(3-propylcarbamoyloxirane-2-carbonyl)-isoleucyl-proline; CHO, aldehyde; Z-, N-benzyloxycarbonyl; AMC, amino-4-methylcoumarin; Ac-, N-acetyl; EDANS, 5-[(2-aminoethyl)amino]naphthalene-1-sulfonyl; DABCYL, 4-dimethylaminoazobenzene-4′-sulfonyl; MES, 2-(N-morpholino)-ethanesulfonic acid; NAGA, β-N-acetylglucosaminidase; PAGE, polyacrylamide gel electrophoresis; RT, reverse transcription; PCR, polymerase chain reaction; TBST, Tris-buffered saline/0.1% Tween 20; AUC, area under the curve; ABP, activity-based probe; L-873724, N-(cyanomethyl)-N2-{(1S)-2,2,2-trifluoro-1-[4'-methylsulfonyl)biphenyl-4-yl]ethyl}-l-leucinamide.

  • ↵ Embedded Image The online version of this article (available at http://molpharm.aspetjournals.org) contains supplemental material.

    • Received June 29, 2007.
    • Revision received October 12, 2007.
  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 73 (1)
Molecular Pharmacology
Vol. 73, Issue 1
1 Jan 2008
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Research ArticleArticle

Effect of Cathepsin K Inhibitor Basicity on in Vivo Off-Target Activities

Sylvie Desmarais, W. Cameron Black, Renata Oballa, Sonia Lamontagne, Denis Riendeau, Paul Tawa, Le Thi Duong, Maureen Pickarski and M. David Percival
Molecular Pharmacology January 1, 2008, 73 (1) 147-156; DOI: https://doi.org/10.1124/mol.107.039511

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Research ArticleArticle

Effect of Cathepsin K Inhibitor Basicity on in Vivo Off-Target Activities

Sylvie Desmarais, W. Cameron Black, Renata Oballa, Sonia Lamontagne, Denis Riendeau, Paul Tawa, Le Thi Duong, Maureen Pickarski and M. David Percival
Molecular Pharmacology January 1, 2008, 73 (1) 147-156; DOI: https://doi.org/10.1124/mol.107.039511
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