Evaluation of 5-(Trifluoromethyl)-1,2,4-oxadiazole-Based Class IIa HDAC Inhibitors for Huntington's Disease.
| Autor: | Stott AJ; Charles River Discovery, Chesterford Research Park, Saffron Walden, Essex CB10 1XL, United Kingdom., Maillard MC; CHDI Management/CHDI Foundation Inc., 6080 Center Drive, Suite 700, Los Angeles, California 90045, United States., Beaumont V; CHDI Management/CHDI Foundation Inc., 6080 Center Drive, Suite 700, Los Angeles, California 90045, United States., Allcock D; Charles River Discovery, Chesterford Research Park, Saffron Walden, Essex CB10 1XL, United Kingdom., Aziz O; Charles River Discovery, Chesterford Research Park, Saffron Walden, Essex CB10 1XL, United Kingdom., Borchers AH; CHDI Management/CHDI Foundation Inc., 6080 Center Drive, Suite 700, Los Angeles, California 90045, United States., Blackaby W; Charles River Discovery, Chesterford Research Park, Saffron Walden, Essex CB10 1XL, United Kingdom., Breccia P; Charles River Discovery, Chesterford Research Park, Saffron Walden, Essex CB10 1XL, United Kingdom., Creighton-Gutteridge G; Charles River Discovery, Chesterford Research Park, Saffron Walden, Essex CB10 1XL, United Kingdom., Haughan AF; Charles River Discovery, Chesterford Research Park, Saffron Walden, Essex CB10 1XL, United Kingdom., Jarvis RE; Charles River Discovery, Chesterford Research Park, Saffron Walden, Essex CB10 1XL, United Kingdom., Luckhurst CA; Charles River Discovery, Chesterford Research Park, Saffron Walden, Essex CB10 1XL, United Kingdom., Matthews KL; Charles River Discovery, Chesterford Research Park, Saffron Walden, Essex CB10 1XL, United Kingdom., McAllister G; Charles River Discovery, Chesterford Research Park, Saffron Walden, Essex CB10 1XL, United Kingdom., Pollack S; Charles River Discovery, Chesterford Research Park, Saffron Walden, Essex CB10 1XL, United Kingdom., Saville-Stones E; Charles River Discovery, Chesterford Research Park, Saffron Walden, Essex CB10 1XL, United Kingdom., Van de Poël AJ; Charles River Discovery, Chesterford Research Park, Saffron Walden, Essex CB10 1XL, United Kingdom., Vater HD; Charles River Discovery, Chesterford Research Park, Saffron Walden, Essex CB10 1XL, United Kingdom., Vann J; Charles River Discovery, Chesterford Research Park, Saffron Walden, Essex CB10 1XL, United Kingdom., Williams R; Charles River Discovery, Chesterford Research Park, Saffron Walden, Essex CB10 1XL, United Kingdom., Yates D; Charles River Discovery, Chesterford Research Park, Saffron Walden, Essex CB10 1XL, United Kingdom., Muñoz-Sanjuán I; CHDI Management/CHDI Foundation Inc., 6080 Center Drive, Suite 700, Los Angeles, California 90045, United States., Dominguez C; CHDI Management/CHDI Foundation Inc., 6080 Center Drive, Suite 700, Los Angeles, California 90045, United States. |
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| Jazyk: | angličtina |
| Zdroj: | ACS medicinal chemistry letters [ACS Med Chem Lett] 2021 Feb 11; Vol. 12 (3), pp. 380-388. Date of Electronic Publication: 2021 Feb 11 (Print Publication: 2021). |
| DOI: | 10.1021/acsmedchemlett.0c00532 |
| Abstrakt: | 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 Competing Interests: The authors declare no competing financial interest. (© 2021 American Chemical Society.) |
| Databáze: | MEDLINE |
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