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

Departments of Biochemistry and Molecular Biology (S.D., S.L., D.R., P.T., M.D.P.) and Medicinal Chemistry (W.C.B., R.O.), Merck Frosst Centre for Therapeutic Research, Kirkland, Quebec, Canada; and Merck Research Laboratories, West Point, Pennsylvania (L.T.D., M.P.)

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.

This article has been cited by other articles:

				S. B. Rodan and L. T. Duong Cathepsin K - A New Molecular Target for Osteoporosis IBMS BoneKEy, January 1, 2008; 5(1): 16 - 24. [Abstract] [Full Text] [PDF]