Structure-Guided Design, Synthesis, and Characterization of Next-Generation Meprin β Inhibitors

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.