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Diego Muñoz-Torrero, PhD

Title: Dual inhibition of soluble epoxide hydrolase and acetylcholinesterase: A new avenue for AD treatment

Abstract: The enzyme soluble epoxide hydrolase (sEH) metabolizes epoxyeicosatrienoic acids (EETs), arachidonic acid metabolites that reduce inflammation and oxidative stress, thereby terminating their beneficial effects. Thus, inhibition of brain sEH should lead to increased levels of EETs, and, hence, to beneficial effects against neuroinflammation. Indeed, brain sEH has been recently validated as a novel target of interest for Alzheimer’s disease (AD) treatment.1 The enzyme acetylcholinesterase (AChE) hydrolyzes the neurotransmitter acetylcholine (ACh), which terminates the cholinergic signaling, and is a validated target of anti-AD drugs. The increased levels of ACh, which result from AChE inhibition, can compensate for the cholinergic deficit that is responsible for the cognitive impairment in AD patients and can also promote arachidonic acid metabolism to EETs, upon activation of ACh muscarinic M1 receptors, thereby potentiating the anti-neuroinflammatory effects of EETs. Thus, we have inferred that the so far unexplored dual inhibition of sEH and AChE might open a new avenue for AD treatment, as it should result in cumulative effects against neuroinflammation and cognitive impairment. Here, we disclose i) the discovery of a first-in-class dual inhibitor of sEH and AChE,2 endowed with in vitro nanomolar potencies toward both enzymes, adequate brain permeability and lack of neurotoxicity, which, despite suboptimal aqueous solubility and microsomal stability, led to beneficial effects on cognition and neuroinflammation in an AD mouse model; and ii) a lead optimization campaign focusing on DMPK properties to identify a better candidate for preclinical development.

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BrazMedChem