Discovery of Highly Selective HDAC2 Inhibitors in Cells That Elevate Histone Acetylation In Vivo without Adverse Effects from Dual Inhibition of HDAC1 and 2

Alzheimer's disease impairs the cognitive domain of learning and memory through synaptic dysfunction. Memory formation requires gene expression to facilitate synaptic plasticity. When HDAC2 is inhibited, elevated histone acetylation promotes the gene expressions critical for synaptic plasticity and thus facilitates memory formation. However, simultaneous inhibition of HDAC1 and HDAC2 leads to hematologic toxicity. As the two isoforms have high homology, it is a challenge to identify selective HDAC2 inhibitors. Here, we report the development of novel cellular assays to determine HDAC2 potency and selectivity over HDAC1. Our HTS campaign using cellular assays for both isoforms identified <b>6</b> as a selective hit compound. With optimization efforts focusing on balancing cellular potency, selectivity, and mitigating BCRP recognition, we discovered compound <b>11,</b> which exhibited significant in vivo efficacy in elevating histone acetylation levels and enhancing LTP. Importantly, <b>11</b> showed no significant hematological toxicity in human blood cells derived from simultaneous inhibition of HDAC1 and HDAC2.