Pyrazole-based cathepsin S inhibitors with improved cellular potency.

High potency pyrazole-based noncovalent inhibitors of human cathepsin S (CatS) were developed by modification of the benzo-fused 5-membered ring heterocycles found in earlier series of CatS inhibitors. Although substitutions on this heterocyclic framework had a moderate impact on enzymatic potency, dramatic effects on cellular activity were observed. Optimization afforded indole- and benzothiophene-derived analogues that were high affinity CatS inhibitors (IC(50)=20-40 nM) with good cellular potency (IC(50)=30-340 nM).