Structure-Guided Design, Synthesis, and Characterization of Next-Generation Meprin β Inhibitors.
Ramsbeck D, Hamann A, Richter G, Schlenzig D, Geissler S, Nykiel V, Cynis H, Schilling S, Buchholz M.
The metalloproteinase meprin β emerged as a current drug target for the treatment of a number of disorders, among those fibrosis, inflammatory bowel disease and Morbus Alzheimer. A major obstacle in the development of metalloprotease inhibitors is target selectivity to avoid side effects by blocking related enzymes with physiological functions. Here, we describe the structure-guided design of a novel series of compounds, based on previously reported highly active meprin β inhibitors. The bioisosteric replacement of the sulfonamide scaffold gave rise to a next generation of meprin inhibitors. Selected compounds based on this novel amine scaffold exhibit high activity against meprin β and also remarkable selectivity over related metalloproteases, i.e., matrix metalloproteases and A disintegrin and metalloproteinases.