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

ABSTRACT: 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 H₁ 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 an

SUBMITTER: Hashimoto K 

PROVIDER: S-EPMC9290043 | biostudies-literature | 2022 Jul

REPOSITORIES: biostudies-literature