Development and characterization of a CNS-penetrant benzhydryl hydroxamic acid class IIa histone deacetylase inhibitor

  • Bioorg Med Chem Lett. 2019 Jan 1;29(1):83-88. doi: 10.1016/j.bmcl.2018.11.009.
Christopher A Luckhurst  1 ,  Omar Aziz  1 ,  Vahri Beaumont  2 ,  Roland W Bürli  1 ,  Perla Breccia  1 ,  Michel C Maillard  3 ,  Alan F Haughan  1 ,  Marieke Lamers  1 ,  Phil Leonard  1 ,  Kim L Matthews  1 ,  Gilles Raphy  1 ,  Andrew J Stott  1 ,  Ignacio Munoz-Sanjuan  2 ,  Beth Thomas  1 ,  Michael Wall  1 ,  Grant Wishart  1 ,  Dawn Yates  1 ,  Celia Dominguez  2
Affiliations
  • 1. Charles River Discovery (previously BioFocus), Chesterford Research Park, Saffron Walden, Essex CB10 1XL, United Kingdom.
  • 2. CHDI Management/CHDI Foundation Inc., 6080 Center Drive, Suite 700, Los Angeles, CA 90045, United States.
  • 3. CHDI Management/CHDI Foundation Inc., 6080 Center Drive, Suite 700, Los Angeles, CA 90045, United States. Electronic address: [email protected].
PMID: 30463802 DOI: 10.1016/j.bmcl.2018.11.009
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.

Keywords
CHDI-390576; CNS-penetrant; Class IIa HDAC inhibitor; HDAC4 inhibition; Hydroxamic acid.
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