4-(3-Trifluoromethylphenyl)-pyrimidine-2-carbonitrile as cathepsin S inhibitors: N3, not N1 is critically important

The N3 nitrogen of the pyrimidine-2-carbonitrile based cathepsin cysteine protease inhibitors is critically important. An 'in situ double activation' mechanism was postulated to explain these results. A novel expanded S2 binding pocket for human cathepsin S enzyme was also identified.