Histone deacetylase 6 inhibitors with blood-brain barrier penetration as a potential strategy for CNS-Disorders therapy

Xiu Gu; Hao Zhang; Minru Jiao; Bo Han; Zixue Zhang; Jianqi Li; Qingwei Zhang

doi:10.1016/j.ejmech.2021.114090

Histone deacetylase 6 inhibitors with blood-brain barrier penetration as a potential strategy for CNS-Disorders therapy

Eur J Med Chem. 2022 Feb 5:229:114090. doi: 10.1016/j.ejmech.2021.114090. Epub 2021 Dec 29.

Authors

Xiu Gu¹, Hao Zhang², Minru Jiao³, Bo Han³, Zixue Zhang³, Jianqi Li³, Qingwei Zhang⁴

Affiliations

¹ Novel Technology Center of Pharmaceutical Chemistry, Shanghai Institute of Pharmaceutical Industry, China State Institute of Pharmaceutical Industry, Shanghai, 201203, China; School of Chemistry & Chemical Engineering, Shanghai University of Engineering Science, Shanghai, 201620, China.
² Novel Technology Center of Pharmaceutical Chemistry, Shanghai Institute of Pharmaceutical Industry, China State Institute of Pharmaceutical Industry, Shanghai, 201203, China; School of Pharmacy, Fudan University, Shanghai, 201203, China.
³ Novel Technology Center of Pharmaceutical Chemistry, Shanghai Institute of Pharmaceutical Industry, China State Institute of Pharmaceutical Industry, Shanghai, 201203, China.
⁴ Novel Technology Center of Pharmaceutical Chemistry, Shanghai Institute of Pharmaceutical Industry, China State Institute of Pharmaceutical Industry, Shanghai, 201203, China. Electronic address: sipiqingwei@163.com.

PMID: 34992037
DOI: 10.1016/j.ejmech.2021.114090

Abstract

Histone deacetylase 6 inhibitors (HDAC6is) have been applied to certain cancer diseases and more recently to central nervous system (CNS) disorders including Rett syndrome, Alzheimer's and Parkinson's diseases, and major depressive disorder. Brain penetrance is the major challenge for the development of HDAC6is as potential therapeutics for CNS disorders due in part to the polarity of hydroxamate ZBG. Hence, only a handful of brain-penetrant HDAC6is have been reported and a few display appropriate in vitro and in vivo activities in models of neurological diseases in last decades. This review summarizes the contemporary research being done on HADC6is with brain penetration both the biological pathways involved and the structural modification attempts.

Publication types

Review

MeSH terms

Animals
Biological Transport
Blood-Brain Barrier / drug effects*
Brain
Central Nervous System Diseases / drug therapy*
Histone Deacetylase 6 / antagonists & inhibitors*
Humans
Hydroxamic Acids / chemistry
Hydroxamic Acids / metabolism
Male
Models, Molecular
Neuroprotective Agents / chemical synthesis*
Neuroprotective Agents / pharmacology
Protein Binding
Protein Conformation
Signal Transduction
Structure-Activity Relationship

Substances

Hydroxamic Acids
Neuroprotective Agents
Histone Deacetylase 6