TY - JOUR A1 - Sellmer, Andreas A1 - Stangl, Hubert A1 - Beyer, Mandy A1 - Grünstein, Elisabeth A1 - Leonhardt, Michel A1 - Pongratz, Herwig A1 - Eichhorn, Emerich A1 - Elz, Sigurd A1 - Striegl, Birgit A1 - Jenei-Lanzl, Zsuzsa A1 - Dove, Stefan A1 - Straub, Rainer H. A1 - Krämer, Oliver H. A1 - Mahboobi, Siavosh T1 - Marbostat-100 Defines a New Class of Potent and Selective Antiinflammatory and Antirheumatic Histone Deacetylase 6 Inhibitors JF - Journal of medicinal chemistry N2 - 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. KW - Animals KW - anti-Inflammatory agent KW - chemical synthesis KW - pharmacology KW - therapeutic use KW - toxicity Y1 - 2018 U6 - https://doi.org/10.1021/acs.jmedchem.7b01593 VL - 61 IS - 8 SP - 3454 EP - 3477 PB - ACS Publications ER -