000191100 001__ 191100
000191100 005__ 20181203023338.0
000191100 0247_ $$2doi$$a10.1021/ml400251g
000191100 022__ $$a1948-5875
000191100 02470 $$2ISI$$a000326367200020
000191100 037__ $$aARTICLE
000191100 245__ $$aFused 3-Hydroxy-3-trifluoromethylpyrazoles Inhibit Mutant Huntingtin Toxicity
000191100 260__ $$bAmer Chemical Soc$$c2013$$aWashington
000191100 269__ $$a2013
000191100 300__ $$a6
000191100 336__ $$aJournal Articles
000191100 520__ $$aHere, we describe the selection and optimization of a chemical series active in both a full-length and a fragment-based Huntington's disease (HD) assay. Twenty-four thousand small molecules were screened in a phenotypic HD assay, identifying a series of compounds bearing a 3-hydroxy-3-trifluoromethylpyrazole moiety as able to revert the toxicity induced by full-length mutant Htt by up to 50%. A chemical exploration around the series led to the identification of compound 4f, which demonstrated to be active in a Htt171-82Qrat primary striatal neuron assay and a PC12-Exon-1 based assay. This compound was selected for testing in R6/2 mice, in which it was well-tolerated and showed a positive effect on body weight and a positive trend in preventing ventricular volume enlargment. These studies provide strong rationale for further testing the potential benefits of 3-hydroxy-3-trifluoromethylpyrazoles in treating HD.
000191100 6531_ $$aHuntington's disease
000191100 6531_ $$amutant Htt toxicity
000191100 6531_ $$aphenotypic screening 3-hydroxy-3-trifluoromethylpyrazoles
000191100 6531_ $$aADME
000191100 6531_ $$aR6/2 mouse model
000191100 700__ $$uSiena Biotech SpA, I-53100 Siena, Italy$$aLa Rosa, Salvatore
000191100 700__ $$uSiena Biotech SpA, I-53100 Siena, Italy$$aBenicchi, Tiziana
000191100 700__ $$uSiena Biotech SpA, I-53100 Siena, Italy$$aBettinetti, Laura
000191100 700__ $$uSiena Biotech SpA, I-53100 Siena, Italy$$aCeccarelli, Ilaria
000191100 700__ $$uSiena Biotech SpA, I-53100 Siena, Italy$$aDiodato, Enrica
000191100 700__ $$uSiena Biotech SpA, I-53100 Siena, Italy$$aFederico, Cesare
000191100 700__ $$uSiena Biotech SpA, I-53100 Siena, Italy$$aFiengo, Pasquale
000191100 700__ $$uSiena Biotech SpA, I-53100 Siena, Italy$$aFranceschini, Davide
000191100 700__ $$aGokce, Ozgun
000191100 700__ $$uSiena Biotech SpA, I-53100 Siena, Italy$$aHeitz, Freddy
000191100 700__ $$uSiena Biotech SpA, I-53100 Siena, Italy$$aLazzeroni, Giulia
000191100 700__ $$0240509$$g158211$$aLuthi-Carter, Ruth
000191100 700__ $$uSiena Biotech SpA, I-53100 Siena, Italy$$aMagnoni, Letizia
000191100 700__ $$uSiena Biotech SpA, I-53100 Siena, Italy$$aMiragliotta, Vincenzo
000191100 700__ $$uSiena Biotech SpA, I-53100 Siena, Italy$$aScali, Carla
000191100 700__ $$aValacchi, Michela$$uSiena Biotech SpA, I-53100 Siena, Italy
000191100 773__ $$j4$$tAcs Medicinal Chemistry Letters$$k10$$q979-984
000191100 909C0 $$0252338$$pLNGF$$xU10838
000191100 909CO $$particle$$ooai:infoscience.tind.io:191100
000191100 937__ $$aEPFL-ARTICLE-191100
000191100 973__ $$rREVIEWED$$sPUBLISHED$$aEPFL
000191100 980__ $$aARTICLE