- Fused 3-hydroxy-3-trifluoromethylpyrazoles inhibit mutant huntingtin toxicity
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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.
- La Rosa, Salvatore,Benicchi, Tiziana,Bettinetti, Laura,Ceccarelli, Ilaria,Diodato, Enrica,Federico, Cesare,Fiengo, Pasquale,Franceschini, Davide,Gokce, Ozgun,Heitz, Freddy,Lazzeroni, Giulia,Luthi-Carter, Ruth,Magnoni, Letizia,Miragliotta, Vincenzo,Scali, Carla,Valacchi, Michela
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supporting information
p. 979 - 984
(2013/10/22)
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- Integration of lead optimization with crystallography for a membrane-bound ion channel target: Discovery of a new class of AMPA receptor positive allosteric modulators
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A novel series of AMPAR positive modulators is described that were identified by high throughput screening. The molecules of the series have been optimized from a high quality starting point hit to afford excellent developability, tolerability, and effica
- Ward, Simon E.,Harries, Mark,Aldegheri, Laura,Austin, Nigel E.,Ballantine, Stuart,Ballini, Elisa,Bradley, Daniel M.,Bax, Benjamin D.,Clarke, Brian P.,Harris, Andrew J.,Harrison, Stephen A.,Melarange, Rosemary A.,Mookherjee, Claudette,Mosley, Julie,Dal Negro, Gianni,Oliosi, Beatrice,Smith, Kathrine J.,Thewlis, Kevin M.,Woollard, Patrick M.,Yusaf, Shahnaz P.
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experimental part
p. 78 - 94
(2011/03/19)
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- COMPOUNDS WHICH POTENTIATE AMPA RECEPTOR AND USES THEREOF IN MEDICINE
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Compounds of formula (I), and salts and solvates thereof are provided: Processes for preparation, pharmaceutical compositions, and uses thereof as a medicament, for example in the treatment of a disease or condition mediated by a reduction or imbalance in glutamate receptor function, such as schizophrenia or cognition impairment, are also disclosed.
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Page/Page column 16
(2010/06/16)
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- COMPOUNDS WHICH POTENTIATE AMPA RECEPTOR AND USES THEREOF IN MEDICINE
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The invention provides compounds of formula (I) and salts thereof wherein R1, R2, R3, R4 and X are as defined in the description. Processes for preparation, pharmaceutical compositions, and uses thereof as a medicament, for example in the treatment of a disease or condition mediated by a reduction or imbalance in glutamate receptor function, such as schizophrenia or cognition impairment, are also disclosed.
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Page/Page column 37
(2009/05/28)
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- COMPOUNDS WHICH POTENTIATE AMPA RECEPTOR AND USES THEREOF IN MEDICINE
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Compound of formula (I) and salts thereof are provided: wherein A, R1, R, R2 are as defined in the specification. Processes for preparation, pharmaceutical compositions, and uses thereof as a medicament, for example in the treatment of a disease or condition mediated by a reduction or imbalance in glutamate receptor function, such as schizophrenia or cognition impairment, are also disclosed.
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Page/Page column 37-38
(2008/12/07)
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