Discovery of Benzylpiperazine Derivatives as CNS-Penetrant and Selective Histone Deacetylase 6 Inhibitors

Inhibition of histone deacetylase 6 (HDAC6) in the brain is a highly attractive therapeutic target for the treatment of neurodegenerative diseases. The low blood-brain barrier permeability of most known HDAC6 inhibitors, however, prevents their application as central nervous system (CNS) drugs. To overcome this problem, we designed and synthesized benzylpiperazine derivatives using a hybrid strategy of combining HDAC6 inhibitors and brain-penetrant histamine H-1 receptor antagonists. Introducing the benzylpiperazine units to the cap region of hydroxamate-type HDAC6 inhibitors led us to identify isozyme-selective and CNS-penetrant HDAC6 inhibitor KH-259 (1) with the appropriate pharmacokinetic and safety properties. Intraperitoneal administration of KH-259 (10 mg/kg) had antidepressant activity and increased acetylated alpha-tubulin in the brain without promoting acetylated histone H3K9. These findings indicate that our hybrid strategy of combining HDAC6 inhibitors and histamine H-1 receptor antagonists is an effective methodology for designing CNS-penetrant HDAC6 inhibitors.

Automated summary

In this study, a hybrid strategy combining HDAC6 inhibitors and brain-penetrant histamine H-1 receptor antagonists was used to design CNS-penetrant HDAC6 inhibitors. The identified compound KH-259 displayed selective inhibition and penetration into the brain, making it a potential therapeutic agent for neurodegenerative diseases.