Project Summary Alzheimer’s disease (AD) is a neurodegenerative disorder that is the primary cause of dementia, the mechanisms of AD have not been completely elucidated and there has yet to yield effective therapy that can prevent, stop or reverse cognitive deficits associated with AD. Epigenetics refers to functional modifications to the genome that do not involve a change in the DNA sequence. Epigenetics became an attractive field in recent years within the drug discovery research communities. Recent preclinical studies also provide robust evidence for the involvement of HDACs in various neurological diseases, and pharmacological treatment aimed at modulating epigenetic regulation. The goal of this application is to develop novel small molecules as HDAC11 selective inhibitor as potential AD therapeutics. In this proposal, we will explore SAR of our leading scaffold to develop a new generation of HDAC11-selective inhibitors (Aim 1), which will be tested to select top compounds with improved PK/PD properties and anti-AD effects using AD preclinical models (Aim 2). Towards the ultimate goal of developing novel HDAC11 inhibitors as effective AD treatments, the end-point of this application is to identify top candidates for Investigational New Drug (IND)-enabling studies.