4354
J. Cai et al. / Bioorg. Med. Chem. Lett. 20 (2010) 4350–4354
G.; Nonomura, K.; Tanabe, K.; Fukaya, H.; Kosaka, T.; Snell, C. R.; Hallet, A.
In vivo pharmacodynamic effect of compound 47 was examined
Bioorg. Med. Chem. Lett. 2008, 18, 3959.
by measuring the accumulation of Lip10 in the spleen of C57Bl/6
mice by western blot after oral dosing. After 4 h compound 47
was shown to significantly induce Lip10 accumulation in the
spleen at doses as low as 0.3 mg/kg (Fig. 5). The lower than Lip10
IC50 free compound level in plasma suggests that this compound
might be sequestered in the lysosome. Further analysis showed
that compound level is ꢀ50-fold greater in spleen than in the
plasma.
In summary, 6-phenyl-1H-imidazo[4,5-c]pyridine-4-carboni-
trile core was identified as a good scaffold for cathepsin S inhibition.
This core offers much improved nitrile war-head stability in com-
parison with other arylnitrile based cathepsin S and K inhibitors.
The optimized compounds have good cellular activity in human JY
cells measured by cathepsin S substrate Lip10 accumulation.
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