Discovery and <i>In Vivo</i> Anti-inflammatory Activity Evaluation of a Novel Non-peptidyl Non-covalent Cathepsin C Inhibitor.
Chen X, Yan Y, Zhang Z, Zhang F, Liu M, Du L, Zhang H, Shen X, Zhao D, Shi JB, Liu X.
Cathepsin C (Cat C) participates in inflammation and immune regulation by affecting the activation of neutrophil serine proteases (NSPs). Therefore, cathepsin C is an attractive target for treatment of NSP-related inflammatory diseases. Here, the complete discovery process of the first potent 'non-peptidyl non-covalent cathepsin C inhibitor' was described with hit finding, structure optimization, and lead discovery. Starting with hit <b>14</b>, structure-based optimization and structure-activity relationship study were comprehensively carried out, and lead compound <b>54</b> was discovered as a potent drug-like cathepsin C inhibitor both <i>in vivo</i> and <i>in vitro</i>. Also, compound <b>54</b> (with cathepsin C Enz IC<sub>50</sub> = 57.4 nM) exhibited effective anti-inflammatory activity in an animal model of chronic obstructive pulmonary disease. These results confirmed that the non-peptidyl and non-covalent derivative could be used as an effective cathepsin C inhibitor and encouraged us to continue further drug discovery on the basis of this finding.