La Rosa, SalvatoreBenicchi, TizianaBettinetti, LauraCeccarelli, IlariaDiodato, EnricaFederico, CesareFiengo, PasqualeFranceschini, DavideGokce, OzgunHeitz, FreddyLazzeroni, GiuliaLuthi-Carter, RuthMagnoni, LetiziaMiragliotta, VincenzoScali, CarlaValacchi, Michela2013-12-092013-12-092013-12-09201310.1021/ml400251ghttps://infoscience.epfl.ch/handle/20.500.14299/97733WOS:000326367200020Here, 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.Huntington's diseasemutant Htt toxicityphenotypic screening 3-hydroxy-3-trifluoromethylpyrazolesADMER6/2 mouse modeltext::journal::journal article::research article