Discovery and In Vivo Proof of Concept of a Highly Potent DualInhibitor of Soluble Epoxide Hydrolase and Acetylcholinesterase forthe Treatment of Alzheimer's Disease

With innumerable clinical failures of target-specific drug candidates for multifactorial diseases, such as Alzheimer'sdisease (AD), which remains inefficiently treated, the advent of multitarget drug discovery has brought a new breath of hope. Here,we disclose a class of 6-chlorotacrine (huprine)-TPPU hybrids as dual inhibitors of the enzymes soluble epoxide hydrolase (sEH)and acetylcholinesterase (AChE), a multitarget profile to provide cumulative effects against neuroinflammation and memoryimpairment. Computational studies confirmed the gorge-wide occupancy of both enzymes, from the main site to a secondary site,including a so far non-described AChE cryptic pocket. The lead compound displayed in vitro dual nanomolar potencies, adequatebrain permeability, aqueous solubility, human microsomal stability, lack of neurotoxicity, and it rescued memory, synaptic plasticity,and neuroinflammation in an AD mouse model, after low dose chronic oral administration.