000191100 001__ 191100
000191100 005__ 20180913062209.0
000191100 0247_ $$2doi$$a10.1021/ml400251g
000191100 022__ $$a1948-5875
000191100 02470 $$2ISI$$a000326367200020
000191100 037__ $$aARTICLE
000191100 245__ $$aFused 3-Hydroxy-3-trifluoromethylpyrazoles Inhibit Mutant Huntingtin Toxicity
000191100 260__ $$aWashington$$bAmer Chemical Soc$$c2013
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_ $$aR6/2 mouse model
000191100 700__ $$aLa Rosa, Salvatore$$uSiena Biotech SpA, I-53100 Siena, Italy
000191100 700__ $$aBenicchi, Tiziana$$uSiena Biotech SpA, I-53100 Siena, Italy
000191100 700__ $$aBettinetti, Laura$$uSiena Biotech SpA, I-53100 Siena, Italy
000191100 700__ $$aCeccarelli, Ilaria$$uSiena Biotech SpA, I-53100 Siena, Italy
000191100 700__ $$aDiodato, Enrica$$uSiena Biotech SpA, I-53100 Siena, Italy
000191100 700__ $$aFederico, Cesare$$uSiena Biotech SpA, I-53100 Siena, Italy
000191100 700__ $$aFiengo, Pasquale$$uSiena Biotech SpA, I-53100 Siena, Italy
000191100 700__ $$aFranceschini, Davide$$uSiena Biotech SpA, I-53100 Siena, Italy
000191100 700__ $$aGokce, Ozgun
000191100 700__ $$aHeitz, Freddy$$uSiena Biotech SpA, I-53100 Siena, Italy
000191100 700__ $$aLazzeroni, Giulia$$uSiena Biotech SpA, I-53100 Siena, Italy
000191100 700__ $$0240509$$aLuthi-Carter, Ruth$$g158211
000191100 700__ $$aMagnoni, Letizia$$uSiena Biotech SpA, I-53100 Siena, Italy
000191100 700__ $$aMiragliotta, Vincenzo$$uSiena Biotech SpA, I-53100 Siena, Italy
000191100 700__ $$aScali, Carla$$uSiena Biotech SpA, I-53100 Siena, Italy
000191100 700__ $$aValacchi, Michela$$uSiena Biotech SpA, I-53100 Siena, Italy
000191100 773__ $$j4$$k10$$q979-984$$tAcs Medicinal Chemistry Letters
000191100 909C0 $$0252338$$pLNGF$$xU10838
000191100 909CO $$ooai:infoscience.tind.io:191100$$particle
000191100 937__ $$aEPFL-ARTICLE-191100
000191100 973__ $$aEPFL$$rREVIEWED$$sPUBLISHED
000191100 980__ $$aARTICLE