Nε-Acryloyllysine Piperazides as Irreversible Inhibitors of Transglutaminase 2– Synthesis, structure-activity relationships and pharmacokinetic profiling

Research output: Contribution to journalResearch articleContributedpeer-review



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 N ε-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.


Original languageEnglish
Pages (from-to)4528-4560
Number of pages33
JournalJournal of medicinal chemistry
Issue number10
Publication statusPublished - 17 Apr 2018

External IDs

Scopus 85046251348



  • Animals, Catalysis, Catalytic Domain, Enzyme Inhibitors/pharmacokinetics, GTP-Binding Proteins/antagonists & inhibitors, Humans, Kinetics, Lysine/analogs & derivatives, Mice, Microsomes, Liver/drug effects, Models, Molecular, Molecular Structure, Protein Conformation, Protein Glutamine gamma Glutamyltransferase 2, Pyridazines/chemistry, Structure-Activity Relationship, Tissue Distribution, Transglutaminases/antagonists & inhibitors