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  • The following term was not found in PubMed: N?-Acryloyllysine.
J Med Chem. 2018 May 24;61(10):4528-4560. doi: 10.1021/acs.jmedchem.8b00286. Epub 2018 May 10.

Nε-Acryloyllysine Piperazides as Irreversible Inhibitors of Transglutaminase 2: Synthesis, Structure-Activity Relationships, and Pharmacokinetic Profiling.

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Institut für Radiopharmazeutische Krebsforschung , Helmholtz-Zentrum Dresden-Rossendorf , Bautzner Landstraße 400 , 01328 Dresden , Germany.
Fakultät Natur- und Umweltwissenschaften , Hochschule Zittau/Görlitz , Theodor-Körner-Allee 16 , 02763 Zittau , Germany.
Fakultät Chemie und Lebensmittelchemie , Technische Universität Dresden , Mommsenstraße 4 , 01062 Dresden , Germany.
Zentrum für Pharmakologie, Medizinische Fakultät , Universität zu Köln , Gleueler Straße 24 , 50931 Köln , Germany.
Structural Bioinformatics, BIOTEC, Technische Universität Dresden , Tatzberg 47-51 , 01307 Dresden , Germany.
Institut für Radiopharmazeutische Krebsforschung, Forschungsstelle Leipzig , Helmholtz-Zentrum Dresden-Rossendorf , Permoserstraße 15 , 04318 Leipzig , Germany.


Transglutaminase 2 (TGase 2)-catalyzed transamidation represents an important post-translational mechanism for protein modification with implications in physiological and pathophysiological conditions, including fibrotic and neoplastic processes. Consequently, this enzyme is considered a promising target for the diagnosis of and therapy for these diseases. In this study, we report on the synthesis and kinetic characterization of Nε-acryloyllysine piperazides as irreversible inhibitors of TGase 2. Systematic structural modifications on 54 new compounds were performed with a major focus on fluorine-bearing substituents due to the potential of such compounds to serve as radiotracer candidates for positron emission tomography. The determined inhibitory activities ranged from 100 to 10 000 M-1 s-1, which resulted in comprehensive structure-activity relationships. Structure-activity correlations using various substituent parameters accompanied by covalent docking studies provide an advanced understanding of the molecular recognition for this inhibitor class within the active site of TGase 2. Selectivity profiling of selected compounds for other transglutaminases demonstrated an excellent selectivity toward transglutaminase 2. Furthermore, an initial pharmacokinetic profiling of selected inhibitors was performed, including the assessment of potential membrane permeability and liver microsomal stability.

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