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Potent, Selective, and CNS-Penetrant Tetrasubstituted Cyclopropane Class IIa Histone Deacetylase (HDAC) Inhibitors

DOI: 10.1021/acsmedchemlett.5b00302 DOI Help
PMID: 26819662 PMID Help

Authors: Christopher A. Luckhurst (BioFocus) , Perla Breccia (BioFocus) , Andrew J. Stott (BioFocus) , Omar Aziz (BioFocus) , Helen L. Birch (BioFocus) , Roland W. Bürli (BioFocus) , Samantha J. Hughes (BioFocus) , Rebecca E. Jarvis (BioFocus) , Marieke Lamers (BioFocus) , Philip M. Leonard (BioFocus) , Kim L. Matthews (BioFocus) , George Mcallister (BioFocus) , Scott Pollack (BioFocus) , Elizabeth Saville-stones (BioFocus) , Grant Wishart (BioFocus) , Dawn Yates (BioFocus) , Celia Dominguez (CHDI Management/CHDI Foundation Inc.)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Acs Medicinal Chemistry Letters , VOL 7 (1) , PAGES 34 - 39

State: Published (Approved)
Published: January 2016

Abstract: Potent and selective class Ha HDAC tetrasubstituted cyclopropane hydroxamic acid inhibitors were identified with high oral bioavailability that exhibited good brain and muscle exposure. Compound 14 displayed suitable properties for assessment of the impact of class Ha HDAC catalytic site inhibition in preclinical disease models.

Journal Keywords: CNS exposure; Class IIa HDAC inhibitors; Huntington’s disease; cyclopropanation; hydroxamic acid; tetrasubstituted cyclopropane

Subject Areas: Biology and Bio-materials


Instruments: I04-Macromolecular Crystallography