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 (IC50 = 20–40 nM) with good cellular potency (IC50 = 30–340 nM).

Graphical abstractNoncovalent, pyrazole-based cathepsin S inhibitors are reported. Significant improvements in cellular potency were achieved through modification of a 4-(indol-3-yl)piperidine head group.Figure optionsDownload full-size imageDownload as PowerPoint slide