- Marbostat-100 Defines a New Class of Potent and Selective Antiinflammatory and Antirheumatic Histone Deacetylase 6 Inhibitors
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Epigenetic modifiers of the histone deacetylase (HDAC) family contribute to autoimmunity, cancer, HIV infection, inflammation, and neurodegeneration. Hence, histone deacetylase inhibitors (HDACi), which alter protein acetylation, gene expression patterns, and cell fate decisions, represent promising new drugs for the therapy of these diseases. Whereas pan-HDACi inhibit all 11 Zn2+-dependent histone deacetylases (HDACs) and cause a broad spectrum of side effects, specific inhibitors of histone deacetylase 6 (HDAC6i) are supposed to have less side effects. We present the synthesis and biological evaluation of Marbostats, novel HDAC6i that contain the hydroxamic acid moiety linked to tetrahydro-β-carboline derivatives. Our lead compound Marbostat-100 is a more potent and more selective HDAC6i than previously established well-characterized compounds in vitro as well as in cells. Moreover, Marbostat-100 is well tolerated by mice and effective against collagen type II induced arthritis. Thus, Marbostat-100 represents a most selective known HDAC6i and the possibility for clinical evaluation of a HDAC isoform-specific drug.
- Sellmer, Andreas,Stangl, Hubert,Beyer, Mandy,Grünstein, Elisabeth,Leonhardt, Michel,Pongratz, Herwig,Eichhorn, Emerich,Elz, Sigurd,Striegl, Birgit,Jenei-Lanzl, Zsuzsa,Dove, Stefan,Straub, Rainer H.,Kr?mer, Oliver H.,Mahboobi, Siavosh
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supporting information
p. 3454 - 3477
(2018/05/01)
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- NOVEL HDAC6 INHIBITORS AND THEIR USES
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The present invention relates to small molecule compounds and their use as HDAC inhibitors and in the treatment of various diseases, such as cancer. The present invention further relates to methods of synthesizing the compounds and methods of treatment. H ? L(HA), H is a head group selected from (head group 1), (head group 2), (head group 3), (head group 4), (head group 5) and (head group 6).
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Page/Page column 121-122
(2016/05/02)
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- Structure-based design of 7-azaindole-pyrrolidine amides as inhibitors of 11β-hydroxysteroid dehydrogenase type i
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Indole-pyrrolidines were identified as inhibitors of 11β- hydroxysteroid dehydrogenase type 1 (11β-HSD1) by high-throughput screening. Optimisation of the initial hit through structure-based design led to 7-azaindole-derivatives, with the best analogues displaying single digit nanomolar IC50 potency. The modeling hypotheses were confirmed by solving the X-ray co-crystal structure of one of the lead compounds. These compounds were selective against 11β-hydroxysteroid dehydrogenase type 2 (selectivity ratio >200) and exhibited good inhibition of 11β-HSD1 (IC50 a cellular model (3T3L1 adipocytes).
- Valeur, Eric,Christmann-Franck, Serge,Lepifre, Franck,Carniato, Denis,Cravo, Daniel,Charon, Christine,Bozec, Sophie,Musil, Djordje,Hillertz, Per,Doare, Liliane,Schmidlin, Fabien,Lecomte, Marc,Schultz, Melanie,Roche, Didier
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p. 5909 - 5914
(2012/11/07)
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- SUBSTITUTED 3-PYRROLIDIN-INDOLE DERIVATIVES
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The invention relates to substituted 3-pyrrolidin-indole derivatives, methods for the production thereof, medicaments containing said compounds, and the use of said substances for producing medicaments, preferably used for the treatment of pain and/or depression.
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Page/Page column 25; 27
(2010/02/11)
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- 4-SUBSTITUTED 1-AMINOCYCLOHEXANE DERIVATIVES FOR UTILIZATION AS ORL1-RECEPTOR AND MU-OPIATE RECEPTOR LIGANDS
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The invention relates to 4-substituted 1-aminocyclohexane derivatives of general formula (I), to a method for the production thereof, to medicaments containing said compounds and to the utilization of 4-substituted 1-aminocyclohexane derivatives for the production of medicaments.
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Page/Page column 26-27
(2008/06/13)
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