Abstract
BackgroundSelective and reversible inhibitors of human Cathepsin K (CatK), including odanacatib (ODN), have been developed as potential therapeutics for the treatment of osteoporosis. Inhibitors of human CatK show significantly less potency for the rodent enzymes compared with that for the human or rabbit enzymes; thus the Schenk model in growing rabbit was developed as a screening assay for the in vivo activity of CatK inhibitors in blocking bone resorption.MethodsIn this study, the efficacy of the selective inhibitors L-833905, L-006235, L-873724, and L-1037536 (ODN) of human CatK in the rapidly growing rabbit ‘Schenk’ model (age seven weeks) was compared to vehicle, using the bisphosphonate, alendronate (ALN), as a positive control, to assess inhibition of bone resorption. An enzyme inhibition assay (EIA) and an in vitro bone resorption assay using rabbit osteoclasts on bovine cortical bone slices were performed to evaluate the potency of these CatK inhibitors. Bone mineral density of the distal femur (DFBMD) was measured after ten days of treatment using ex vivo DXA densitometry.ResultsResults of the EIA using rabbit CatK and the rabbit bone resorption assay showed that three of the four compounds (L-006235, L-873724, and ODN) had similar potencies in the reduction of collagen degradation. L-833905 appeared to be a weaker inhibitor of CatK. Taking into account the respective in vitro potencies and pharmacokinetic profiles via oral administration, the efficacy of these four CatK inhibitors was demonstrated in a dose-related manner in the growing rabbit. Significant increases in DFBMD in animals dosed with the CatK inhibitors compared to vehicle were seen.ConclusionsEfficacy of the CatK inhibitors in the Schenk rabbit correlated well with that in the in vitro rabbit bone resorption assay and in the ovariectomized rabbit model as previously published. Hence, these studies validated the rabbit Schenk assay as a rapid and reliable in vivo model for prioritizing human CatK inhibitors as potential therapeutic agents.
Highlights
Selective and reversible inhibitors of human Cathepsin K (CatK), including odanacatib (ODN), have been developed as potential therapeutics for the treatment of osteoporosis
Experiments using ALN at 50, 100, 200, or 500 μg/kg/day SC for ten consecutive days showed significant increases in Distal femur bone mineral density (DFBMD) above vehicle, ranging from 15% at 50 μg/kg/day (p < 0.01) to 21% at 500 μg/kg/day (p < 0.001) (Table 1)
We previously described the development of the adult OVX rabbit assay to assess the efficacy of CatK inhibitors on preventing estrogen deficiency bone loss in the lumbar vertebrae and distal femur [15]
Summary
Selective and reversible inhibitors of human Cathepsin K (CatK), including odanacatib (ODN), have been developed as potential therapeutics for the treatment of osteoporosis. Inhibitors of human CatK show significantly less potency for the rodent enzymes compared with that for the human or rabbit enzymes; the Schenk model in growing rabbit was developed as a screening assay for the in vivo activity of CatK inhibitors in blocking bone resorption. The utility of the OVX rat is limited by significant interspecies sequence variation (88% homology) in key residues within the active site of human and rat CatK enzymes [12]; inhibitors of human CatK have significantly lower potency against the rodent CatK enzyme to be reliably tested for bone effects in the rat or mouse model. The selection of rabbit as the preclinical species for in vivo screening assay for CatK inhibitors was due to the species differences in response to this class of bone resorption inhibitors. Due to the long duration of the adult OVX rabbit model and the relatively large size of adult rabbits (3.5 kg), the use of the adult OVX rabbit model for quick in vivo screening and selection of compounds with limited drug quantity in the early preclinical phase is impractical
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