Development of soluble epoxide hydrolase inhibitors for the treatment of Alzheimer's disease

This is a multidisciplinary effort to develop soluble epoxide hydrolase inhibitors (sEHIs) as a novel treatment approach for Alzheimer's disease. Elevated levels of the sEH protein have been observed in patients with Alzheimer's disease, and inhibition of sEH presents a promising therapeutic mechanism. However, existing sEHI molecules, despite demonstrating high potency, generally exhibit poor predicted blood-brain barrier penetration, limiting their ability to reach the central nervous system at therapeutic concentrations. With support from a $3.1 million grant awarded by the National Institutes on Aging and preliminary backing from the MSU Molecular Discovery Grant program, Dr. Lee has assembled a team that spans pharmacology, toxicology, chemistry, translational neuroscience, biochemistry and molecular biology and biostatistics to address this critical barrier to efficacy.

The project will systematically explore how structural modifications to sEHI molecules influence their ability to cross the blood-brain barrier and enhance CNS exposure. The team will implement a design-test-learn strategy, leveraging in-house assays to evaluate sEHI potency, binding kinetics and in vitro pharmacokinetic parameters. Top candidates from these screens will advance to in vivo pharmacokinetic studies to quantify systemic and CNS exposure. Iterative optimization will be used to fine-tune the most promising sEHI modifications, focusing on drug-like properties and the capacity to achieve robust brain target engagement. A central goal is to identify sEHIs that can block at least 90% of brain sEH activity at low doses, a benchmark that will guide selection of candidates for efficacy testing in animal models of Alzheimer's disease.

Preliminary work under MSU's Molecular Discovery Grant program helped establish the collaborative framework and initial data that justified the larger National Institutes on Aging award. If successful, the project aims not only to deliver candidate sEHIs suitable for preclinical testing but also to demonstrate a translational path for sEHI-based therapeutics that more effectively reach and engage brain targets.

Current Alzheimer's treatment options only marginally slow progression and cannot reverse damage, leaving patients and families with a chronic, costly disease trajectory. Beyond Alzheimer's, this  work can improve sEHI technology and strategies for CNS delivery could inform diagnostic and therapeutic development for other neurodegenerative disorders, such as Parkinson's disease. This work integrates targeted chemical design with rigorous pharmacokinetic and pharmacodynamic evaluation to confront a key obstacle blood-brain barrier penetration aiming to produce therapeutics that meaningfully alter disease course and reduce long-term burdens on patients and society.