Heteroaromatic Inhibitors of the Astacin Proteinases Meprin α, Meprin β and Ovastacin Discovered by a Scaffold‐Hopping Approach

• DOI: 10.1002/cmdc.202000822
• Publication Date: 2020-12-24T17:12:58Z
• Authors: Kathrin Tan; Christian Jäger; Hagen Körschgen; Stefanie Geissler; Dagmar Schlenzig; Mirko Buchholz; Walter Stöcker; Daniel Ramsbeck
• Keywords: 0301 basic medicine; Dose-Response Relationship, Drug; Molecular Structure; Cell Survival; Metalloendopeptidases; Antineoplastic Agents; Full Papers; Hydrocarbons, Aromatic; Recombinant Proteins; Structure-Activity Relationship; 03 medical and health sciences; Drug Discovery; Metalloproteases; Tumor Cells, Cultured; Humans; Protease Inhibitors; Amines; Drug Screening Assays, Antitumor

Astacin metalloproteinases, in particular meprins α and β, as well ovastacin, are emerging drug targets. Drug-discovery efforts have led to the development of first potent selective inhibitors last few years. However, most recent compounds based on a highly flexible tertiary amine scaffold that could cause metabolic liabilities or decreased potency due entropic penalty upon binding target. Thus, aim this study was discover novel conformationally constrained scaffolds starting points for further inhibitor optimization. Shifting from amines rigid heteroaromatic cores resulted boost inhibitory activity. Moreover, some already exhibited higher activity against individual astacin proteinases compared recently reported also favorable off-target selectivity profile, thus qualifying them very suitable chemical probes target validation.