Evaluation of 5-(Trifluoromethyl)-1,2,4-oxadiazole-Based Class IIa HDAC Inhibitors for Huntington's Disease
| Autor: | Elizabeth Anne Saville-Stones, Alexander H. Borchers, David Allcock, Wesley Blackaby, Gillian Creighton-Gutteridge, Andrew J. Stott, Ignacio Munoz-Sanjuan, Julie Vann, Rebecca E. Jarvis, Dawn Yates, Celia Dominguez, Amanda Van de Poël, Vahri Beaumont, Michel Maillard, Scott Pollack, Rachel Williams, Christopher A. Luckhurst, Huw D. Vater, Omar Aziz, Alan Findlay Haughan, George McAllister, Kim L. Matthews, Perla Breccia |
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| Rok vydání: | 2020 |
| Předmět: |
Trifluoromethyl
010405 organic chemistry Organic Chemistry Oxadiazole Computational biology medicine.disease 01 natural sciences Biochemistry Class (biology) 0104 chemical sciences 010404 medicinal & biomolecular chemistry chemistry.chemical_compound Huntington's disease chemistry Drug Discovery medicine |
| Zdroj: | ACS Med Chem Lett |
| ISSN: | 1948-5875 |
| Popis: | [Image: see text] Using an iterative structure–activity relationship driven approach, we identified a CNS-penetrant 5-(trifluoromethyl)-1,2,4-oxadiazole (TFMO, 12) with a pharmacokinetic profile suitable for probing class IIa histone deacetylase (HDAC) inhibition in vivo. Given the lack of understanding of endogenous class IIa HDAC substrates, we developed a surrogate readout to measure compound effects in vivo, by exploiting the >100-fold selectivity compound 12 exhibits over class I/IIb HDACs. We achieved adequate brain exposure with compound 12 in mice to estimate a class I/IIb deacetylation EC(50), using class I substrate H4K12 acetylation and global acetylation levels as a pharmacodynamic readout. We observed excellent correlation between the compound 12 in vivo pharmacodynamic response and in vitro class I/IIb cellular activity. Applying the same relationship to class IIa HDAC inhibition, we estimated the compound 12 dose required to inhibit class IIa HDAC activity, for use in preclinical models of Huntington’s disease. |
| Databáze: | OpenAIRE |
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