title: Fused 3-Hydroxy-3-trifluoromethylpyrazoles Inhibit Mutant Huntingtin Toxicity.
abstract: Here, 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 Htt171-82Q rat 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.
authors.affiliation: Siena Biotech SpA , Strada del Petriccio e Belriguardo 35, 53100 Siena, Italy.
authors.forename: Salvatore
authors.initials: S
authors.lastname: La Rosa
authors.affiliation: Siena Biotech SpA , Strada del Petriccio e Belriguardo 35, 53100 Siena, Italy.
authors.forename: Tiziana
authors.initials: T
authors.lastname: Benicchi
authors.affiliation: Siena Biotech SpA , Strada del Petriccio e Belriguardo 35, 53100 Siena, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Bettinetti
authors.affiliation: Siena Biotech SpA , Strada del Petriccio e Belriguardo 35, 53100 Siena, Italy.
authors.forename: Ilaria
authors.initials: I
authors.lastname: Ceccarelli
authors.affiliation: Siena Biotech SpA , Strada del Petriccio e Belriguardo 35, 53100 Siena, Italy.
authors.forename: Enrica
authors.initials: E
authors.lastname: Diodato
authors.affiliation: Siena Biotech SpA , Strada del Petriccio e Belriguardo 35, 53100 Siena, Italy.
authors.forename: Cesare
authors.initials: C
authors.lastname: Federico
authors.affiliation: Siena Biotech SpA , Strada del Petriccio e Belriguardo 35, 53100 Siena, Italy.
authors.forename: Pasquale
authors.initials: P
authors.lastname: Fiengo
authors.affiliation: Siena Biotech SpA , Strada del Petriccio e Belriguardo 35, 53100 Siena, Italy.
authors.forename: Davide
authors.initials: D
authors.lastname: Franceschini
authors.affiliation: Brain Mind Institute , École Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland.
authors.forename: Ozgun
authors.initials: O
authors.lastname: Gokce
authors.affiliation: Siena Biotech SpA , Strada del Petriccio e Belriguardo 35, 53100 Siena, Italy.
authors.forename: Freddy
authors.initials: F
authors.lastname: Heitz
authors.affiliation: Siena Biotech SpA , Strada del Petriccio e Belriguardo 35, 53100 Siena, Italy.
authors.forename: Giulia
authors.initials: G
authors.lastname: Lazzeroni
authors.affiliation: Brain Mind Institute , École Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland.
authors.forename: Ruth
authors.initials: R
authors.lastname: Luthi-Carter
authors.affiliation: Siena Biotech SpA , Strada del Petriccio e Belriguardo 35, 53100 Siena, Italy.
authors.forename: Letizia
authors.initials: L
authors.lastname: Magnoni
authors.affiliation: Siena Biotech SpA , Strada del Petriccio e Belriguardo 35, 53100 Siena, Italy.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Miragliotta
authors.affiliation: Siena Biotech SpA , Strada del Petriccio e Belriguardo 35, 53100 Siena, Italy.
authors.forename: Carla
authors.initials: C
authors.lastname: Scali
authors.affiliation: Siena Biotech SpA , Strada del Petriccio e Belriguardo 35, 53100 Siena, Italy.
authors.forename: Michela
authors.initials: M
authors.lastname: Valacchi
keywords: 3-hydroxy-3-trifluoromethylpyrazoles; ADME; Huntington’s disease; R6/2 mouse model; mutant Htt toxicity; phenotypic screening