| Literature DB >> 30463802 |
Christopher A Luckhurst1, Omar Aziz1, Vahri Beaumont2, Roland W Bürli1, Perla Breccia1, Michel C Maillard3, Alan F Haughan1, Marieke Lamers1, Phil Leonard1, Kim L Matthews1, Gilles Raphy1, Andrew J Stott1, Ignacio Munoz-Sanjuan2, Beth Thomas1, Michael Wall1, Grant Wishart1, Dawn Yates1, Celia Dominguez2.
Abstract
We have identified a potent, cell permeable and CNS penetrant class IIa histone deacetylase (HDAC) inhibitor 22, with >500-fold selectivity over class I HDACs (1,2,3) and ∼150-fold selectivity over HDAC8 and the class IIb HDAC6 isoform. Dose escalation pharmacokinetic analysis demonstrated that upon oral administration, compound 22 can reach exposure levels in mouse plasma, muscle and brain in excess of cellular class IIa HDAC IC50 levels for ∼8 h. Given the interest in aberrant class IIa HDAC function for a number of neurodegenerative, neuromuscular, cardiac and oncology indications, compound 22 (also known as CHDI-390576) provides a selective and potent compound to query the role of class IIa HDAC biology, and the impact of class IIa catalytic site occupancy in vitro and in vivo.Entities:
Keywords: CHDI-390576; CNS-penetrant; Class IIa HDAC inhibitor; HDAC4 inhibition; Hydroxamic acid
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Year: 2018 PMID： 30463802 DOI： 10.1016/j.bmcl.2018.11.009
Source DB: PubMed Journal: Bioorg Med Chem Lett ISSN： 0960-894X Impact factor: 2.823