Publications (14)31.3 Total impact
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Article: Investigation of imatinib and other approved drugs as starting points for antidiabetic drug discovery with FXR modulating activity.
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ABSTRACT: A self-organizing map (SOM) is a virtual screening method used for correlation of molecular structure and potential biological activity on a certain target and offers a way to represent multi-dimensional data of large databases in a two-dimensional space. Large databases, for example the DrugBank database, provide information about biological activity and chemical structure of small molecules and are widely used in drug development for identification of new lead structures. The farnesoid X receptor (FXR) is a ligand activated transcription factor involved in key regulation mechanisms within glucose and lipid homeostasis. Although FXR became an established target in drug development for diseases associated with lipid, glucose or hepatic disorders during the last decade, none of the developed compounds have reached later phases of clinical development so far. We used a SOM trained with known FXR ligands to screen the DrugBank database for potential ligands for FXR. In this article, we report the successful identification of six approved drugs out of the Drugbank as FXR modulators (ketoconazole, pentamidine, dobutamine, imatinib, papaverine and montelukast) by using a SOM for screening of the DrugBank database. We show FXR modulation by selected compounds in a full length FXR transactivation assay and modulation of a FXR target gene by imatinib.Biochemical pharmacology 03/2012; 83(12):1674-81. · 4.25 Impact Factor -
Article: SAR studies of acidic dual γ-secretase/PPARγ modulators.
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ABSTRACT: A novel set of dual γ-secretase/PPARγ modulators characterized by a 2-benzyl hexanoic acid scaffold is presented. Synthetic efforts were focused on the variation of the substitution pattern of the central benzene. Finally, we obtained a new class of 2,5-disubstituted 2-benzylidene hexanoic acid derivatives, which act as dual γ-secretase/PPARγ modulators in the low micromolar range. We have explored broad SAR and successfully improved the dual pharmacological activity and the selectivity profile against potential off-targets such as NOTCH and COX. Compound 17 showed an IC(50) Aβ42=2.4 μM and an EC(50) PPARγ=7.2 μM and could be a valuable tool to further evaluate the concept of dual γ-secretase/PPARγ modulators in animal models of Alzheimer's disease.Bioorganic & medicinal chemistry 08/2011; 19(18):5372-82. · 2.82 Impact Factor -
Article: Resveratrol Reduces Hepatic Fat Accumulation by Modulating Farnesoid X Receptor Signaling
Gastroenterology 01/2011; 140(5). · 11.68 Impact Factor -
Article: Dimethylcelecoxib inhibits mPGES-1 promoter activity by influencing EGR1 and NF-κB.
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ABSTRACT: DMC (dimethylcelecoxib={4-[5-(2,5-dimethylphenyl)-3(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide}) is a close derivative of celecoxib, without cyclooxygenase inhibiting properties up to very high concentrations. Nevertheless, after stimulation of various human cell lines with IL-1β/TNFα and simultaneous treatment with DMC PGE(2) synthesis is inhibited [1]. Here we investigated the effect of DMC on mPGES-1 promoter activity, using a reporter gene assay. Our data demonstrate that DMC inhibits mPGES-1 promoter activity by blocking nuclear EGR1 expression and repressing NF-κB transcriptional activity. Other putative transcription factors, known to regulate mPGES-1 expression, such as SP1 or CREB are not affected by DMC. Over-expression of EGR1 completely prevents the inhibitory effect of DMC on mPGES-1 promoter activity, indicating that the repressing effect of DMC on mPGES-1 expression is mainly dependent on blocking EGR1 expression. mPGES-1, EGR1 and NF-κB are important proteins involved in many pathological conditions such as inflammation and cancer. Therefore, DMC seems to be a promising substance to treat inflammatory and carcinogenic processes, although it does not inhibit cyclooxygenases.Biochemical pharmacology 11/2010; 80(9):1365-72. · 4.25 Impact Factor -
Article: Design, synthesis, and biological evaluation of a novel class of gamma-secretase modulators with PPARgamma activity.
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ABSTRACT: We present a novel class of dual modulators of gamma-secretase and peroxisome proliferator-activated receptor gamma (PPARgamma) based on the structure of 2-(bis(phenethoxy)pyrimidine-2-ylthio)hexanoic acid 8 (IC(50)(Abeta42) = 22.8 microM, EC(50)(PPARgamma) = 8.3 microM). The modulation of both targets with approved drugs (i.e., amyloid-beta 42 (Abeta42)-lowering NSAIDs for gamma-secretase and glitazones for PPARgamma) has demonstrated beneficial effects in in vitro and in vivo models of Alzheimer's disease (AD). However, although NSAIDs and PPARgamma agonists share similar structural features, no druglike compounds with dual activities as gamma-secretase modulators (GSMs) and PPARgamma agonists have been designed so far. On the basis of our initial lead structure 8, we present the structure-activity relationships (SARs) of broad structural variations. A significant improvement was reached by the introduction of p-trifluoromethyl substituents at the phenyl residues yielding compound 16 (IC(50)(Abeta42) = 6.0 microM, EC(50)(PPARgamma) = 11.0 microM) and the replacement of the two phenyl residues of 8 by cyclohexyl yielding compound 22 (IC(50)(Abeta42) = 5.1 microM, EC(50)(PPARgamma) = 6.6 microM).Journal of Medicinal Chemistry 06/2010; 53(12):4691-700. · 4.80 Impact Factor -
Article: Design, Synthesis, and Biological Evaluation of a Novel Class of γ-Secretase Modulators with PPARγ Activity
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ABSTRACT: We present a novel class of dual modulators of γ-secretase and peroxisome proliferator-activated receptor γ (PPARγ) based on the structure of 2-(bis(phenethoxy)pyrimidine-2-ylthio)hexanoic acid 8 (IC50(Aβ42) = 22.8 μM, EC50(PPARγ) = 8.3 μM). The modulation of both targets with approved drugs (i.e., amyloid-β 42 (Aβ42)-lowering NSAIDs for γ-secretase and glitazones for PPARγ) has demonstrated beneficial effects in in vitro and in vivo models of Alzheimer’s disease (AD). However, although NSAIDs and PPARγ agonists share similar structural features, no druglike compounds with dual activities as γ-secretase modulators (GSMs) and PPARγ agonists have been designed so far. On the basis of our initial lead structure 8, we present the structure−activity relationships (SARs) of broad structural variations. A significant improvement was reached by the introduction of p-trifluoromethyl substituents at the phenyl residues yielding compound 16 (IC50(Aβ42) = 6.0 μM, EC50(PPARγ) = 11.0 μM) and the replacement of the two phenyl residues of 8 by cyclohexyl yielding compound 22 (IC50(Aβ42) = 5.1 μM, EC50(PPARγ) = 6.6 μM).05/2010; -
Article: Antidiabetic sulfonylureas modulate farnesoid X receptor activation and target gene transcription.
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ABSTRACT: The sulfonylureas glibenclamide and glimepiride are oral antidiabetic drugs that stimulate insulin secretion by closing pancreatic ATP-dependent potassium channels. The farnesoid X receptor (FXR) is a ligand-activated transcription factor that regulates the expression of several target genes involved in bile acid metabolism and lipid and glucose homeostasis. In this study we investigated the potential effects of sulfonylureas on the signaling of FXR using a reporter-gene assay, real-time qPCR and computational methods such as molecular docking and molecular dynamic simulations. We demonstrate that glibenclamide and glimepiride modulate FXR activation in a reporter-gene assay and induce FXR target genes in HepG2 cells. Within the docking experiments and molecular dynamics simulation, we found glibenclamide interacting with the ligand-binding domain of FXR and with helix 12. Glibenclamide and glimepiride are potential ligands of FXR and modulate activation and signaling.Future medicinal chemistry 04/2010; 2(4):575-86. · 2.52 Impact Factor -
Article: [New classes of drugs in the pipeline. New in the treatment of diabetes mellitus].
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ABSTRACT: Die Pharmakotherapie des Diabetes mellitus hat in der letzten Dekade kontinuierlich zugenommen. Die Insulinverordnungen haben sich in diesem Zeitraum verdoppelt. Die Metformin-Verordnungen sind mehr als dreifach angestiegen, wohingegen die der Sulfonylharnstoffe seit 1999 in etwa konstant geblieben sind. Glitazone zeigen nur mehr geringfügige Zuwachsraten, da insbesondere neuere Studien Hinweise auf ein erhöhtes Herzinfarkt- und Frakturrisiko gezeigt haben.Pharmazie in unserer Zeit 03/2010; 39(2):142-6. -
Article: Rational design of a pirinixic acid derivative that acts as subtype-selective PPARgamma modulator.
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ABSTRACT: Peroxisome proliferator-activated receptor gamma (PPARgamma) is involved in glucose and lipid homeostasis. PPARgamma agonists are in clinical use for the treatment of type 2 diabetes. Lately, a new class of selective PPARgamma modulators (SPPARgammaMs) was developed, which are believed to show less side effects than full PPARgamma agonists. We have previously shown that alpha-substitution of pirinixic acid, a moderate agonist of PPARalpha and PPARgamma, leads to low micromolar active balanced dual agonists of PPARalpha and PPARgamma. Herein we present modifications of pirinixic acid leading to subtype-selective PPARgamma agonists and furthermore the development of a selective PPARgamma modulator guided by molecular docking studies.Bioorganic & medicinal chemistry letters 03/2010; 20(8):2469-73. · 2.65 Impact Factor -
Article: Truxillic acid derivatives act as peroxisome proliferator-activated receptor gamma activators.
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ABSTRACT: In previous studies, we identified a truxillic acid derivative as selective activator of the peroxisome proliferator-activated receptor gamma, which is a member of the nuclear receptor family and acts as ligand-activated transcription factor of genes involved in glucose metabolism. Herein we present the structure-activity relationships of 16 truxillic acid derivatives, investigated by a cell-based reporter gene assay guided by molecular docking analysis.Bioorganic & medicinal chemistry letters 03/2010; 20(9):2920-3. · 2.65 Impact Factor -
Article: Target Profile Prediction: Cross‐Activation of Peroxisome Proliferator‐Activated Receptor (PPAR) and Farnesoid X Receptor (FXR)
Molecular Informatics. 02/2010; 29(4):287 - 292. -
Article: From machine learning to natural product derivatives that selectively activate transcription factor PPARgamma.
ChemMedChem 02/2010; 5(2):191-4. · 3.15 Impact Factor -
Article: From Machine Learning to Natural Product Derivatives that Selectively Activate Transcription Factor PPARγ
ChemMedChem 01/2010; 5(2):191-194. · 3.15 Impact Factor -
Article: Discovery of a novel class of 2-mercaptohexanoic acid derivatives as highly active PPARalpha agonists.
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ABSTRACT: A novel and robust scaffold for highly active PPARalpha agonists based on the 2-mercaptohexanoic acid substructure is presented. Systematic structural variation of the substitution pattern of the phenolic backbone yielded detailed SAR especially of ortho and meta substituents. We corroborated the importance of the sulfur atom as well as of the n-butyl chain for PPARalpha activity in the 2-mercaptohexanoic acid head group by preparation of carbon analogs and alpha-unsubstituted derivatives. Compound 10 represents a low nano molar active PPARalpha activator with excellent selectivity towards PPARgamma.Bioorganic & medicinal chemistry letters 06/2009; 19(15):4421-6. · 2.65 Impact Factor -
Article: Novel Pirinixic Acids as PPARα Preferential Dual PPARα/γ Agonists
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ABSTRACT: Pirinixic acid is a moderate agonist of both the alpha and the gamma subtype of the peroxisome proliferator activated receptor (PPAR). Previously, we have shown that -alkyl substitution leads to balanced low micromolar-active dual agonists of PPAR and PPAR. Taking -hexyl pirinixic acid as a new scaffold, we further optimized PPAR activity by enlargement of the lipophilic backbone by substituting the 2,3-dimethylphenyl with biphenylic moieties. Such a substitution pattern had only minor impact on PPAR activity but further increased PPAR activity leading to nanomolar activities. Supporting docking studies proposed that the (R)-enantiomer should fit the PPAR ligand-binding pocket better and thus be more active than the (S)-enantiomer. Single enantiomers of selected active analogues were then prepared by enantio-selective synthesis and enantio-selective preparative HPLC, respectively. Biological data for the distinct enantiomers fully corroborated the docking experiments and substantiate a stereochemical impact on PPAR activation.QSAR & Combinatorial Science 03/2009; 28(5):576 - 586. · 1.55 Impact Factor -
Article: [High-throughput screening for inhibitors of bacterial transglycosylase].
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ABSTRACT: Vor dem Hintergrund zahlreicher bestehender und sich schnell neu entwickelnder Resistenzen von Keimen gegenüber Antibiotika - klinisch besonders relevant bei multiresistenten Problemkeimen wie Staphylococcus aureus oder Streptococcus pneumoniae - kommt der Suche nach neuen Antibiotika und der Aufklärung von Wirkmechanismen höchste Priorität zu. Ein wichtiger Schritt ist nun Forschern in Taiwan gelungen, indem sie die Bindung von Moenomycin an sein Target, die bakterielle Transglykosylase, charakterisiert und aus den erhaltenen Ergebnissen eine Methode für ein High-Throughput-Screening für neue Antibiotika entwickelt haben.Pharmazie in unserer Zeit 02/2008; 37(4):278-9.
Top Journals
Institutions
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2009–2012
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Goethe-Universität Frankfurt am Main
- Institut für Organische Chemie und Chemische Biologie
Frankfurt am Main, Hesse, Germany
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2008
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Frankfurt Zoo
Frankfurt am Main, Hesse, Germany
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