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

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Abstract Alzheimer’s disease affects 6 million Americans, is the 6th leading cause of death in the nation and substantially impacts patients’ quality of life with no effective cure available. As the population over the age of 65 is projected to triple by 2035, the number of Alzheimer’s disease patients is expected to increase by at least two-fold. Therefore, there is an unmet medical need to develop novel treatments to prevent and or cure Alzheimer’s disease. Recent studies indicate that soluble epoxide hydrolase (sEH) is a novel therapeutic target for Alzheimer’s disease. Although the newer sEH inhibitors have sub-nanomolar potency, they generally suffer from poor blood- brain barrier penetration and unsuitable physical properties. As a high percentage of sEH inhibition / engagement is needed to elicit significant biological activity, sEH inhibitors with high blood-brain barrier penetration and exposure are needed. Although the structure-activity relationships (SARs) of sEH inhibitors have been extensively investigated, their impact on blood-brain barrier penetration has rarely been studied and the existing clinical candidates are predicted to have poor CNS exposure. While most of the SAR studies focus on the substituents on both ends of the inhibitors, the linker of the inhibitors has rarely been explored. We will investigate how modifications of sEHI’s linker and other modifications affect its CNS drug-like properties and CNS exposure. We will then systematically incorporate the optimized modifications to further improve sEHI’s drug-like properties and CNS exposure. Aim 1 of this project will apply a novel design-test-learn strategy to guide the design of the novel sEHIs using our in- house assays to screen sEHIs potency, binding kinetics and in vitro pharmacokinetic parameters. The top candidates will be screened for their PK properties and CNS exposure using our established low dose oral cassette dosing methodology. We will then further determine the detailed pharmacokinetic properties and CNS exposure parameters of the selected candidates. As the program progresses, we will our observations for further optimization. The optimized candidates will be selected based on the new sEHIs’ potency, binding kinetics, CNS drug-like properties, pharmacokinetic parameters and CNS target engagement for the in vivo efficacy testing. In Aim 2, the optimized sEHIs will be subjected to a 7-day dose range finding experiment and the sEHI, which can inhibit at least 90% of brain sEH with the lowest dose, will be selected for testing in mouse and rat Alzheimer’s disease models to determine their efficacy.