Discovery and In Vivo Proof of Concept of a Highly Potent Dual Inhibitor of Soluble Epoxide Hydrolase and Acetylcholinesterase for the Treatment of Alzheimer’s Disease

With innumerable
clinical failures of target-specific drug candidates
for multifactorial diseases, such as Alzheimer’s disease (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 memory impairment. 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, adequate
brain 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.