Identification of Potent and
Selective Cathepsin S
Inhibitors Containing Different Central Cyclic Scaffolds
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Abstract
Starting from the weakly active dual
CatS/K inhibitor <b>5</b>, structure-based design supported
by X-ray analysis led to the discovery
of the potent and selective (>50 000-fold vs CatK) cyclopentane
derivative <b>22</b> by exploiting specific ligand–receptor
interactions in the S2 pocket of CatS. Changing the central cyclopentane
scaffold to the analogous pyrrolidine derivative <b>57</b> decreased
the enzyme as well as the cell-based activity significantly by 24-
and 69-fold, respectively. The most promising scaffold identified
was the readily accessible proline derivative (e.g., <b>79</b>). This compound, with an appealing ligand efficiency (LE) of 0.47,
included additional structural modifications binding in the S1 and
S3 pockets of CatS, leading to favorable in vitro and in vivo properties.
Compound <b>79</b> reduced IL-2 production in a transgenic DO10.11
mouse model of antigen presentation in a dose-dependent manner with
an ED<sub>50</sub> of 5 mg/kg