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Structure-guided design, synthesis, and characterization of next-generation meprin β inhibitors

: Ramsbeck, Daniel; Hamann, Antje; Richter, Georg; Schlenzig, Dagmar; Geißler, Stefanie; Nykiel, Vera; Cynis, Holger; Schilling, Stephan; Buchholz, Mirko


Journal of medicinal chemistry 61 (2018), Nr.10, S.4578-4592
ISSN: 0022-2623
ISSN: 1520-4804
Fraunhofer IZI ()

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.