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Your search keyword '"Lammerhofer M."' showing total 17 results
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17 results on '"Lammerhofer M."'

1. Extract from gum resin of Boswellia serrata decreases [IA.sub.2]-antibody in a patient with 'Late onset Autoimmune Diabetes of the Adult' (LADA)

Author

Schrott, E., Laufer, S., Lammerhofer, M., and Ammon, H.P.T.

Subjects
Case studies, Health aspects, Autoimmune diseases -- Case studies, Diabetes mellitus -- Case studies, Boswellia -- Health aspects, Plant extracts -- Health aspects, Herbal medicine -- Case studies, Diabetes -- Case studies, Materia medica, Vegetable -- Health aspects, Medicine, Botanic -- Case studies, Medicine, Herbal -- Case studies
Abstract

Type 1 diabetes and the Late onset Autoimmune Diabetes of the Adult (LADA) are autoimmune diseases where a chronic inflammation of pancreatic islets causes [beta]-cell apoptosis leading to insulin deficiency. [...] more...

Published
2014
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14. Addressing a Trapped High-Energy Water: Design and Synthesis of Highly Potent Pyrimidoindole-Based Glycogen Synthase Kinase-3β Inhibitors

Author

Stanislav Andreev, Christian Geibel, Ahmed El-Gokha, Jenny Romasco, Niclas Kahlke, Francesco Ansideri, Stefan Knapp, Michael Lämmerhofer, Stefan Laufer, Lukas Grätz, Andrea Tarozzi, Giulia Sita, Roberta Tesch, Pierre Koch, Tatu Pantsar, Andreev S., Pantsar T., Tesch R., Kahlke N., El-Gokha A., Ansideri F., Gratz L., Romasco J., Sita G., Geibel C., Lammerhofer M., Tarozzi A., Knapp S., Laufer S.A., and Koch P. more...

Subjects
Molecular Dynamics Simulation, Neuroblastoma, Structure-Activity Relationship, GSK-3, Drug Discovery, Tumor Cells, Cultured, Humans, Kinome, Binding site, Glycogen synthase, Protein Kinase Inhibitors, GSK3B, IC50, Cell Proliferation, Glycogen Synthase Kinase 3 beta, biology, Chemistry, Autophosphorylation, Water, Pyrimidines, N/A, Drug Design, biology.protein, Biophysics, Molecular Medicine, Small molecule binding
Abstract

In small molecule binding, water is not a passive bystander but rather takes an active role in the binding site, which may be decisive for the potency of the inhibitor. Here, by addressing a high-energy water, we improved the IC50 value of our co-crystallized glycogen synthase kinase-3β (GSK-3β) inhibitor by nearly two orders of magnitude. Surprisingly, our results demonstrate that this high-energy water was not displaced by our potent inhibitor (S)-3-(3-((7-ethynyl-9H-pyrimido[4,5-b]indol-4-yl)(methyl)amino)piperidin-1-yl)propanenitrile ((S)-15, IC50 value of 6 nM). Instead, only a subtle shift in the location of this water molecule resulted in a dramatic decrease in the energy of this high-energy hydration site, as shown by the WaterMap analysis combined with microsecond timescale molecular dynamics simulations. (S)-15 demonstrated both a favorable kinome selectivity profile and target engagement in a cellular environment and reduced GSK-3 autophosphorylation in neuronal SH-SY5Y cells. Overall, our findings highlight that even a slight adjustment in the location of a high-energy water can be decisive for ligand binding. more...

Published
2021
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15. Discovery and evaluation of enantiopure 9H-pyrimido[4,5‐b]indoles as nanomolar GSK‐3β inhibitors with improved metabolic stability

Author

Stanislav Andreev, Tatu Pantsar, Ahmed El-Gokha, Francesco Ansideri, Mark Kudolo, Débora Bublitz Anton, Giulia Sita, Jenny Romasco, Christian Geibel, Michael Lämmerhofer, Márcia Ines Goettert, Andrea Tarozzi, Stefan A. Laufer, Pierre Koch, Andreev S., Pantsar T., El-gokha A., Ansideri F., Kudolo M., Anton D.B., Sita G., Romasco J., Geibel C., Lammerhofer M., Goettert M.I., Tarozzi A., Laufer S.A., and Koch P. more...

Subjects
Male, 9H‐pyrimido[4,5‐b] indole, Indoles, 9H-pyrimido[4,5-b]indole, Drug Evaluation, Preclinical, CHO Cells, Molecular Dynamics Simulation, Article, Protein kinase, Cell Line, glycogen synthase kinase-3β, lcsh:Chemistry, Structure-Activity Relationship, Cricetulus, Drug Stability, Glycogen synthase kinase‐3β, Drug Discovery, Animals, Humans, lcsh:QH301-705.5, Protein Kinase Inhibitors, Kinase inhibitor, Glycogen Synthase Kinase 3 beta, lcsh:Biology (General), lcsh:QD1-999, Microsomes, Liver, Female, Metabolic stability
Abstract

Glycogen synthase kinase-3&beta, (GSK-3&beta, ) is a potential target in the field of Alzheimer&rsquo, s disease drug discovery. We recently reported a new class of 9H-pyrimido[4,5-b]indole-based GSK-3&beta, inhibitors, of which 3-(3-((7-chloro-9H-pyrimido[4,5-b]indol-4-yl)(methyl)amino)piperidin-1-yl)propanenitrile (1) demonstrated promising inhibitory potency. However, this compound underwent rapid degradation by human liver microsomes. Starting from 1, we prepared a series of amide-based derivatives and studied their structure&ndash, activity relationships against GSK-3&beta, supported by 1 &micro, s molecular dynamics simulations. The biological potency of this series was substantially enhanced by identifying the eutomer configuration at the stereocenter. Moreover, the introduction of an amide bond proved to be an effective strategy to eliminate the metabolic hotspot. The most potent compounds, (R)-3-(3-((7-chloro-9H-pyrimido[4,5-b]indol-4-yl)(methyl)amino)piperidin-1-yl)-3-oxopropanenitrile ((R)-2) and (R)-1-(3-((7-bromo-9Hpyrimido[4,5-b]indol-4-yl)(methyl)amino)piperidin-1-yl)propan-1-one ((R)-28), exhibited IC50 values of 480 nM and 360 nM, respectively, and displayed improved metabolic stability. Their favorable biological profile is complemented by minimal cytotoxicity and neuroprotective properties. more...

Published
2020

16. Statin Treatment Is Associated with Alterations in the Platelet Lipidome.

Author

Harm T, Frey M, Dittrich K, Goldschmied A, Rohlfing AK, Fu X, Brun A, Castor T, Rath D, Müller K, Lammerhofer M, and Gawaz M

Subjects
Humans, Blood Platelets metabolism, Lipidomics, Triglycerides metabolism, Glycerophospholipids metabolism, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Coronary Artery Disease metabolism, Acute Coronary Syndrome metabolism
Abstract

Background:  Platelets are key players in the pathophysiology of coronary artery disease (CAD) and platelet hyperreactivity leads to increased risk of developing adverse cardiovascular events. Further, significant changes in the platelet lipidome occur in patients with acute coronary syndrome (ACS) and critically regulated lipids lead to platelet hyperresponsiveness. Statin treatment is crucial in the treatment and prevention of patients with CAD by remodeling lipid metabolism., Objective:  In this study, we investigate the platelet lipidome of CAD patients by untargeted lipidomics, highlighting significant changes between statin-treated and naïve patients., Methods:  We characterized the platelet lipidome in a CAD cohort ( n  = 105) by an untargeted lipidomics approach using liquid chromatography coupled to mass spectrometry., Results:  Among the annotated lipids, 41 lipids were significantly upregulated in statin-treated patients, whereas 6 lipids were downregulated compared to naïve patients. The most prominent upregulated lipids in statin-treated patients belong to the class of triglycerides, cholesteryl esters, palmitic acid, and oxidized phospholipids, whereas mainly glycerophospholipids were downregulated compared to untreated patients. A more pronounced effect of statin treatment on the platelet lipidome was observed in ACS patients. We further highlight a dose-dependent influence on the platelet lipidome., Conclusion:  Our results reveal that the platelet lipidome is altered in CAD patients with statin treatment and upregulated lipids embody mainly characteristic triglycerides, whereas downregulated lipids mostly compromise glycerophospholipids, which may play a role in the pathophysiology of CAD. Results of this study may contribute to the understanding of statin treatment softening the lipid phenotype., Competing Interests: None declared., (Thieme. All rights reserved.) more...

Published
2023
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17. Enantiomeric separation of N-protected amino acids by non-aqueous capillary electrophoresis using quinine or tert-butyl carbamoylated quinine as chiral additive.

Author

Piette V, Lammerhofer M, Lindner W, and Crommen J

Subjects
Electrophoresis, Capillary, Quinine, Stereoisomerism, Amino Acids analysis
Abstract

A capillary electrophoretic (CE) method for the enantioseparation of N-protected chiral amino acids was developed using quinine and tert-butyl carbamoylated quinine as chiral selectors added to nonaqueous electrolyte solutions (NACE). A series of various N-derivatized amino acids were tested as chiral selectands, and in order to optimize the CE enantioseparation of these compounds, different parameters were investigated: the nature of the organic solvent, the combination of different solvents, the nature and the concentration of the background electrolyte, the selector concentration, the capillary temperature, and the applied voltage. The influence of these factors on the separation of the analyte enantiomers and the electroosmotic flow was studied. Generally, with tert-butyl carbamoylated quinine as chiral selector, better enantioseparations were achieved than with unmodified quinine. Optimum experimental conditions were found with a buffer made of 12. 5 mM ammonia, 100 mM octanoic acid, and 10 mM tert-butyl carbamoylated quinine in an ethanol-methanol mixture (60:40 v/v). Under these conditions, DNB-Leu enantiomers could be separated with a selectivity factor (alpha) of 1.572 and a resolution (Rs) of 64.3; a plate number (N) of 127,000 and an asymmetry factor (As) of 0.93 were obtained for the first migrating enantiomer., (Copyright 1999 Wiley-Liss, Inc.) more...

Published
1999
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