1H-imidazo[4,5-c]pyridine-4-carbonitrile as cathepsin S inhibitors: separation of desired cellular activity from undesired tissue accumulation through optimization of basic nitrogen pka.

Abstract Based on the theoretical understanding of the in vivo lysosomotropism, by adjusting the p k a of basic nitrogen containing cathepsin S inhibitors, a set of compounds with p k a  6–8 were identified to have excellent cell based Lip10 activity, yet avoiding undesired sequestration in spleen.