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

• Published in: Molecular pharmacology 2008-01, Vol.73 (1), p.147-156
• Main Authors: Desmarais, Sylvie, Black, W Cameron, Oballa, Renata, Lamontagne, Sonia, Riendeau, Denis, Tawa, Paul, Duong, Le Thi, Pickarski, Maureen, Percival, M David
• Format: Article
• Language: English
• Subjects: Animals; Cathepsin K; Cathepsins - antagonists & inhibitors; Enzyme Inhibitors - pharmacology; Mice
• ISSN: 0026-895X; 1521-0111
• DOI: 10.1124/mol.107.039511

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, 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.