Histone deacetylase 6 inhibitors in Alzheimer's disease therapy: structure design and challenges.

Recently, histone deacetylases 6 (HDAC6) has been extensively studied for involvement in pathogenesis of central nervous system (CNS) diseases, especially for Alzheimer's disease (AD). A lot of literatures have disclosed that HDAC6 inhibitors (HDAC6is) are effective and promising in AD treatment. Though many HDAC6is were reported, only a handful of them displayed appropriate in vivo activities in models of neurological diseases. BBB permeability and off-target toxicity are the major obstacle and challenge for the development of available HDAC6is. In this review, we summarized recent brain-permeable HDAC6is from drug design perspective, and discussed the challenges and structural modification attempts in developing HDAC6is with better blood-brain barrier (BBB) permeability.