Design and synthesis of novel cathepsin C inhibitors with anti-inflammatory activity.

Cathepsin C (Cat C) is a potential candidate for addressing inflammatory conditions associated with neutrophil serine proteases (NSPs). The high reactivity of electrophilic warheads and the metabolic instability of peptide structures are among the primary challenges in developing potent cathepsin C inhibitors. Compound 36, a lead compound derived from compound 1 through structure-based drug design and structure-activity relationship (SAR), exhibited strong Cat C inhibitory activity with an IC(50) value of 437 nM. It also showed a substantial enhancement in overall anti-inflammatory activity, achieving an inhibitory effect on NO release at 4.1 μM. Furthermore, molecular docking was conducted to analyze the mode of action with Cat C. And cell thermal shift analysis (CETSA) revealed that this compound increases the temperature tolerance of Cat C in a concentration-dependent manner, suggesting strong binding to the target Cat C. Prolonged pharmacological inhibition activity may result in the depletion of active NSPs.