Effect of Cathepsin K Inhibitor Basicity on in Vivo Off-Target Activities
| العنوان: | Effect of Cathepsin K Inhibitor Basicity on in Vivo Off-Target Activities |
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| المؤلفون: | Maureen Pickarski, Denis Riendeau, Paul Tawa, Le Thi Duong, Sonia Lamontagne, W. Cameron Black, M. David Percival, Renata Oballa, Sylvie Desmarais |
| المصدر: | Molecular Pharmacology. 73:147-156 |
| بيانات النشر: | American Society for Pharmacology & Experimental Therapeutics (ASPET), 2007. |
| سنة النشر: | 2007 |
| مصطلحات موضوعية: | Pharmacology, Cathepsin, Chemistry, Cathepsin K, Cathepsins, Cysteine protease, Cathepsin B, Cathepsin C, Mice, Biochemistry, Cathepsin O, Cathepsin H, In vivo, Animals, Molecular Medicine, Enzyme Inhibitors |
| الوصف: | 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)- N 2-{(1 S )-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. |
| تدمد: | 1521-0111 0026-895X |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::61a7d4edad73f4f59f727b1a27283b6c https://doi.org/10.1124/mol.107.039511 |
| رقم الأكسشن: | edsair.doi.dedup.....61a7d4edad73f4f59f727b1a27283b6c |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15210111 0026895X |
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