Pyrazole-based arylalkyne cathepsin S inhibitors. Part II: Optimization of cellular potency

Basic lipophilic substituents dramatically improved the cellular potency of a previously disclosed series of pyrazole-based arylalkyne cathepsin S inhibitors. The incorporation of substituted benzylamines in the para position of the arylalkyne maintained enzymatic activity (hCatS IC50 = 80–420 nM) and imparted cellular potency (IC50 = 0.8–4.0 μM). Further refinement of the morpholine portion of the pharmacophore enabled the identification of bicyclic piperidines with enhanced affinity for CatS (IC50 = 10–30 nM) and sub-micromolar cellular potency (JY Ii IC50 = 200–720 nM).

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