Structure‐based design and in vivo anti‐arthritic activity evaluation of a potent cyclopropyl peptidyl nitrile inhibitor of cathepsin C

Abstract

Cathepsin C (CatC) is a dipeptidyl‐exopeptidase which activates neutrophil serine protease precursors (elastase, proteinase 3, cathepsin G and NSP4) by removing their N‐terminal propeptide in bone marrow cells at the promyelocytic stage of neutrophil differentiation. The resulting active neutrophil serine proteases are implicated in chronic inflammatory and autoimmune diseases. Hence, inhibition of CatC represents a therapeutic strategy to suppress excessive neutrophil serine protease activities in various neutrophil mediated diseases. We designed and synthesized a series of peptidyl cyclopropyl nitrile compounds as putative CatC inhibitors. One of these compounds, IcatC ((S)‐2‐amino‐N‐((1R,2R)‐1‐cyano‐2‐(4′‐(4‐methylpiperazin‐1‐ylsulfonyl)biphenyl‐4‐yl)cyclopro‐pyl)butanamide)) was identified as a cell‐permeable and potent inhibitor of both human and rodent CatC. Pharmacokinetic analysis in mice showed that IcatC was retained in the bone marrow and reached sufficient tissue levels for CatC inhibition. Subcutaneous administration of IcatC in a mouse model of rheumatoid arthritis induced by monoclonal anti‐collagen antibodies exhibited statistically significant anti‐arthritic activity, with sustained reductions in mean total arthritis scores, mean rear paw arthritis scores and mean rear paw thickness.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.