Wodtke, Robert ORCID: 0000-0001-7462-7111, Hauser, Christoph, Ruiz-Gomez, Gloria, Jaeckel, Elisabeth, Bauer, David, Lohse, Martin, Wong, Alan, Pufe, Johanna, Ludwig, Friedrich-Alexander, Fischer, Steffen, Hauser, Sandra ORCID: 0000-0001-8206-6000, Greif, Dieter, Pisabarro, M. Teresa, Pietzsch, Jens ORCID: 0000-0002-1610-1493, Pietsch, Markus and Loeser, Reik (2018). N-epsilon-Acryloyllysine Piperazides as Irreversible Inhibitors of Transglutaminase 2: Synthesis, Structure-Activity Relationships, and Pharmacokinetic Profiling. J. Med. Chem., 61 (10). S. 4528 - 4561. WASHINGTON: AMER CHEMICAL SOC. ISSN 1520-4804

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Abstract

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-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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Wodtke, RobertUNSPECIFIEDorcid.org/0000-0001-7462-7111UNSPECIFIED
Hauser, ChristophUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ruiz-Gomez, GloriaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Jaeckel, ElisabethUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bauer, DavidUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lohse, MartinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wong, AlanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Pufe, JohannaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ludwig, Friedrich-AlexanderUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Fischer, SteffenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hauser, SandraUNSPECIFIEDorcid.org/0000-0001-8206-6000UNSPECIFIED
Greif, DieterUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Pisabarro, M. TeresaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Pietzsch, JensUNSPECIFIEDorcid.org/0000-0002-1610-1493UNSPECIFIED
Pietsch, MarkusUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Loeser, ReikUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-185997
DOI: 10.1021/acs.jmedchem.8b00286
Journal or Publication Title: J. Med. Chem.
Volume: 61
Number: 10
Page Range: S. 4528 - 4561
Date: 2018
Publisher: AMER CHEMICAL SOC
Place of Publication: WASHINGTON
ISSN: 1520-4804
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
HYDROGEN-BOND BASICITY; IN-VITRO MODEL; TISSUE TRANSGLUTAMINASE; COVALENT INHIBITORS; KINETIC CHARACTERIZATION; BIOLOGICAL EVALUATION; ACCURATE PREDICTION; ARTIFICIAL MEMBRANE; ARYL HALIDES; NITRO-GROUPSMultiple languages
Chemistry, MedicinalMultiple languages
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/18599

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