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Desmarais S, Black WC, Oballa R, Lamontagne S, Riendeau D, Tawa P, Duong le T, Pickarski M, Percival MD: Effect of cathepsin k inhibitor basicity on in vivo off-target activities. Mol Pharmacol. 2008 Jan;73(1):147-56. Epub 2007 Oct 16.
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)-{(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, (125) I-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. |
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