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

Abstract

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.

Unveiling the Multitarget Anti-Alzheimer Drug Discovery Landscape: A Bibliometric Analysis

“…As previously mentioned, sEH inhibitors reduce neuroinflammation and Aβ and tau pathologies and display cognition-enhancing effects in different mouse models of AD [ 67 ]. Very recently, we have reported the first class of dual inhibitors of sEH/AChE [ 77 ]. The design rationale was that inhibition of AChE, apart from leading to cognitive improvement, increases the levels of the neurotransmitter acetylcholine, which, in turn, may promote the metabolism of arachidonic acid to the anti-inflammatory EETs, i.e., the same effects that arise from sEH inhibition, by a different mechanism.…”

A Combined Chronic Low-Dose Soluble Epoxide Hydrolase and Acetylcholinesterase Pharmacological Inhibition Promotes Memory Reinstatement in Alzheimer’s Disease Mice Models

“…to deep into the molecular mechanisms that underlie the beneficial effects promoted by dual treatment. In analogy with our previous work that demonstrated beneficial effects in SAMP8 mice with the aforementioned dual acting TPPU-6-chlorotacrine hybrid compound [19]. Here, we decided to explore a combination based on the same constituting drugs of that hybrid, i.e., TPPU [23] and 6-chlorotacrine (6-Cl-THA) [24], using the same AD mouse model.…”

“…In the present study, we aimed (i) to explore the potential of a drug combination strategy based on sEH and AChE inhibition; (ii) to further support dual inhibition of sEH and AChE as a new general therapeutic strategy against neuroinflammation and cholinergic deficits; and (iii) to deep into the molecular mechanisms that underlie the beneficial effects promoted by dual treatment. In analogy with our previous work that demonstrated beneficial effects in SAMP8 mice with the aforementioned dual acting TPPU-6-chlorotacrine hybrid compound [19]. Here, we decided to explore a combination based on the same constituting drugs of that hybrid, i.e., TPPU [23] and 6-chlorotacrine (6-Cl-THA) [24], using the same AD mouse model.…”

“…Very interestingly, the cholinergic system is linked to the production of EETs. Indeed, activating muscarinic M1 receptors by the neurotransmitter acetylcholine (ACh) promotes the metabolism of arachidonic acid to EETs [ 19 , 20 ]. Thus, the increased levels of ACh upon AChE inhibition should lead to increased levels of EETs, and hence, to potentiation of their anti-neuroinflammatory effects.…”

“…Thus, dual inhibition of sEH and AChE should result in additive or synergistic effects against neuroinflammation, a critical early mechanism of AD, and beneficial effects on cognition. Based on these premises, we have recently demonstrated that a chronic low dose of a dual inhibitor, targeting sEH and AChE (i.e., a multitarget compound), was able to rescue cognitive decline, AD hallmarks and synaptic dysfunction in SAMP8, a mouse model of late-onset AD (LOAD) [ 19 ].…”