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

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posted on 25.04.2018, 00:00 by Daniel Ramsbeck, Antje Hamann, Georg Richter, Dagmar Schlenzig, Stefanie Geissler, Vera Nykiel, Holger Cynis, Stephan Schilling, Mirko Buchholz
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.