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First insight into structure-activity relationships of selective meprin beta inhibitors

: Ramsbeck, D.; Hamann, A.; Schlenzig, D.; Schilling, S.; Buchholz, M.


Bioorganic & medicinal chemistry letters 27 (2017), No.11, pp.2428-2431
ISSN: 0960-894X
ISSN: 1464-3405
Journal Article
Fraunhofer IZI ()

The astacin proteases meprin a and beta are emerging drug targets for treatment of disorders such as kidney failure, fibrosis or inflammatory bowel disease. However, there are only few inhibitors of both proteases reported to date. Starting from NNGH as lead structure, a detailed elaboration of the structure-activity relationship of meprin beta inhibitors was performed, leading to compounds with activities in the lower nanomolar range. Considering the preference of meprin 0 for acidic residues in the P1' position, the compounds were optimized. Acidic modifications induced potent inhibition and >100-fold selectivity over other structurally related metalloproteases such as MMP-2 or ADAM10.