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  • 1
    Language: English
    In: Trends in Pharmacological Sciences, 2010, Vol.31(9), pp.402-410
    Description: γ-Secretase is a key enzyme in the pathophysiology of Alzheimer's disease (AD) and is responsible for the production of potentially toxic amyloid-β (Aβ) 42 peptides. γ-Secretase modulators (GSMs) are small molecules (〈600 Da) causing a product shift from Aβ42 toward shorter and less toxic Aβ fragments. Classical non-steroidal anti-inflammatory drugs (NSAIDs) constituted the first class of GSMs, and therefore many of today's GSMs exhibit NSAID-like overall structure combining an acidic head group with a lipophilic backbone. Recent developments include structurally different non-acidic GSMs. Here we summarize common structural features of GSMs, pick up the controversial discussion regarding their mechanism of action, and show how computational analysis of pharmacophoric features can help reveal their pharmacological profile.
    Keywords: Pharmacy, Therapeutics, & Pharmacology
    ISSN: 0165-6147
    E-ISSN: 1873-3735
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  • 2
    Language: English
    In: Angewandte Chemie International Edition, April 22, 2013, Vol.52(17), p.4676(6)
    Description: Byline: Birgit Spankuch, Sarah Keppner, Lisa Lange, Tiago Rodrigues, Heiko Zettl, Christian P. Koch, Michael Reutlinger, Markus Hartenfeller, Petra Schneider, Gisbert Schneider Keywords: drug design; enzyme inhibitors; fragment-based design; Polo-like kinase; virtual synthesis ***** No abstract is available for this article. ***** Author Affiliation: Departement Chemie und Angewandte Biowissenschaften, Eidgenossische Technische Hochschule (ETH), Wolfgang-Pauli-Strasse 10, 8093 Zurich (Switzerland) http://www.modlab.ethz.ch Universitatsfrauenklinik, Molekulare Onkologie und Gynakologie, Eberhard Karls Universitat, Calwerstrasse 7, 72076 Tubingen (Germany) Departement Chemie und Angewandte Biowissenschaften, Eidgenossische Technische Hochschule (ETH), Wolfgang-Pauli-Strasse 10, 8093 Zurich (Switzerland) http://www.modlab.ethz.ch Article Note: We thank Dr. M. Bieler for computing QED values and Sarah Haller for technical support. Dr. T. Geppert performed the computational docking experiment. Dr. M. Rupp contributed the ISOAK similarity function to DOGS. This research was financially supported by the Deutsche Krebshilfe (grant no. 108651), the Wilhelm-Sander-Stiftung (grant no. 2009.024.1), the Messer-Stiftung (to B.S.), the Swiss National Science Foundation (grant no. 205321-134783), and the Deutsche Forschungsgemeinschaft (grant no. FOR1406TP4) (to G.S.). B.S. is grateful to Dr. D. Wallwiener for providing working facilities. G.S. is grateful to the Chemical Computing Group, Inc. (Montreal, Canada) for a research license of MOE. Supporting information: Additional Supporting Information may be found in the online version of this article As a service to our authors and readers, this journal provides supporting information supplied by the authors. Such materials are peer reviewed and may be re-organized for online delivery, but are not copy-edited or typeset. Technical support issues arising from supporting information (other than missing files) should be addressed to the authors.
    Keywords: Enzyme Inhibitors ; Enzymes ; Cancer Treatment
    ISSN: 1433-7851
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  • 3
    Language: English
    In: Bioorganic & Medicinal Chemistry Letters, 01 August 2009, Vol.19(15), pp.4421-4426
    Description: SAR of a novel and robust scaffold for highly active PPARα agonists based on the 2-mercaptohexanoic acid substructure are presented. A novel and robust scaffold for highly active PPARα 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 and substituents. We corroborated the importance of the sulfur atom as well as of the -butyl chain for PPARα activity in the 2-mercaptohexanoic acid head group by preparation of carbon analogs and α-unsubstituted derivatives. Compound represents a low nano molar active PPARα activator with excellent selectivity towards PPARγ.
    Keywords: Ppar ; 2-Mercaptohexanoic Acid ; SAR ; Pparα Agonists ; Medicine ; Chemistry ; Anatomy & Physiology
    ISSN: 0960-894X
    E-ISSN: 1464-3405
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  • 4
    Language: English
    In: Bioorganic & Medicinal Chemistry, 2011, Vol.19(11), pp.3394-3401
    Description: 5-Lipoxygenase (5-LO) and microsomal prostaglandin E synthase (mPGES)-1 are key enzymes in the biosynthesis of leukotrienes and prostaglandin (PG)E , respectively, and are considered as valuable targets for the treatment of inflammatory diseases. Here, we present the identification of 2-mercaptohexanoic acid derivatives as dual inhibitors of 5-LO and mPGES-1. The lead compound 2(4-(3-biphenyloxypropoxy)phenylthio)hexanoic acid ( ) inhibits human 5-LO and mPGES-1 in cell-free assays with an IC = 3.5 and 2.2 μM, respectively, and suppresses 5-LO in intact cells with even a higher potency (IC = 0.9 μM). Compound (10 μM) neither significantly inhibited the related 12- or 15-LOs nor cyclooxygenase-1 and -2 or cytosolic phospholipase A . Based on the selective and potent inhibition of 5-LO and mPGES-1, further assessment of these 2-mercaptohexanoic acids in preclinical models of inflammation are warranted.
    Keywords: 5-Lipoxygenase ; Leukotriene ; Neutrophils ; Inflammation ; Prostaglandin ; Medicine ; Chemistry ; Anatomy & Physiology
    ISSN: 0968-0896
    E-ISSN: 1464-3391
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  • 5
    Language: English
    In: Bioorganic & Medicinal Chemistry, 15 September 2011, Vol.19(18), pp.5372-5382
    Description: 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 showed an IC Aβ42 = 2.4 μM and an EC 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.
    Keywords: SAR ; Alzheimer’s Disease ; Pparγ Agonists ; Γ-Secretase Modulators ; Carboxylic Acids ; Medicine ; Chemistry ; Anatomy & Physiology
    ISSN: 0968-0896
    E-ISSN: 1464-3391
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  • 6
    Language: English
    In: Macromolecules, 05/11/2010, Vol.43(9), pp.4268-4274
    Keywords: Chemistry;
    ISSN: 0024-9297
    E-ISSN: 1520-5835
    Source: American Chemical Society (via CrossRef)
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  • 7
    Language: English
    In: Angewandte Chemie International Edition, 22 April 2013, Vol.52(17), pp.4676-4681
    Description: of the anticancer target Polo‐like kinase 1 was found by computer‐based molecular design. This type II kinase inhibitor was synthesized as suggested by the design software DOGS and exhibited significant antiproliferative effects against HeLa cells without affecting nontransformed cells. The study provides a proof‐of‐concept for reaction‐based de novo design as a leading tool for drug discovery.
    Keywords: Drug Design ; Enzyme Inhibitors ; Fragment‐Based Design ; Polo‐Like Kinase ; Virtual Synthesis
    ISSN: 1433-7851
    E-ISSN: 1521-3773
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  • 8
    Language: German
    In: Pharmazie in unserer Zeit, March 2010, Vol.39(2), pp.108-113
    Description: Die mittlerweile als “Epidemie des 21. Jahrhunderts” bezeichnete Volkskrankheit Typ 2 Diabetes mellitus (T2DM) zählt mehr denn je zu den großen Herausforderungen bei der Entwicklung neuer Arzneistoffe. Die beiden jüngsten Arzneistoffklassen – Analoga des Glucagon‐like peptide‐1 (GLP‐1) und Inhibitoren der Dipeptidyl‐Peptidase IV (DPP IV) – sollen aufgrund ihres pharmakologischen Ansatzes klassische Antidiabetika‐assoziierte Nebenwirkungen wie Hypoglykämien und Gewichtszunahme umgehen.
    Keywords: Diabetes Mellitus, Type 2–Drug Therapy ; Dipeptidyl-Peptidase IV Inhibitors–Pharmacology ; Glucagon-Like Peptide 1–Therapeutic Use ; Humans–Analogs & Derivatives ; Hypoglycemic Agents–Pharmacology ; Incretins–Therapeutic Use ; Incretins–Pharmacology ; Incretins–Therapeutic Use ; Incretins–Physiology ; Dipeptidyl-Peptidase IV Inhibitors ; Hypoglycemic Agents ; Incretins ; Glucagon-Like Peptide 1;
    ISSN: 0048-3664
    E-ISSN: 1615-1003
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  • 9
    Language: English
    In: Alzheimer's & Dementia: The Journal of the Alzheimer's Association, 01 July 2012, Vol.8(4), pp.P105-P106
    Description: To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.jalz.2012.05.268 Byline: Thorsten Jumpertz (1), Andreas Rennhack (2), Julia Ness (1), Sandra Baches (1), Heiko Zettl (3), Claus Pietrzik (4), Bruno Bulic (5) Author Affiliation: (1) Heinrich-Heine-University, Dusseldorf, Germany (2) Center of Advanced European Studies and Research, Bonn, Germany (3) Brown University, Providence, Rhode Island, United States (4) University Medical Center of the Johannes Gutenberg-University, Mainz, Germany (5) Center for Advanced European Studies and Research, Bonn, Germany Article Note: (miscellaneous) O1-11-06
    ISSN: 1552-5260
    E-ISSN: 1552-5279
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  • 10
    Language: English
    In: The journal of physical chemistry. B, 14 July 2005, Vol.109(27), pp.13397-401
    Description: We show that noncovalently bound dye molecules can be used as labels in single-molecule fluorescence experiments for the determination of aggregate formation in standard surfactant systems. Aqueous solutions of sulfosuccinic acid bis(2-ethylhexyl) ester sodium salt, hexadecyltrimethylammonium chloride, and pentaethylene glycol monododecyl ether have been studied by fluorescence correlation spectroscopy using commercially available dyes. The translational diffusion coefficient and the critical micelle concentrations have been determined and compare well to values reported in the literature. The respective charges of the surfactant and of the dye molecule are crucial for the effectiveness of the presented method.
    Keywords: Micelles -- Research ; Fluorescence -- Usage ; Surface Active Agents -- Research;
    ISSN: 1520-6106
    E-ISSN: 15205207
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