Novel Soluble Epoxide Hydrolase Inhibitors for the Treatment of Alzheimer's Disease
Alzheimer’s disease (AD) is the most common cause of dementia and one of the leading causes of death in the United States. AD is the only leading cause of death for which no disease-modifying therapy is currently available. Neuroinflammation plays a major role in AD pathogenesis. Epoxyeicosanoid signaling is a key integrator of cell-cell communication in the central nervous system (CNS), coordinating cellular responses across different cell types. Epoxyeicosatrienoic acids (EETs) are arachidonic acid metabolites of cytochrome P450 epoxygenase that have potent anti-inflammatory activity.
In collaboration with Dr. Zheng’s group at Baylor, we demonstrated that pharmacological inhibition of sEH can attenuate neuroinflammation, enhance reduction of plaque pathology, and eventually reverse spatial learning and memory deficits in preclinical models of AD. Although some sEH inhibitors (sEHIs) have been reported, none of them are optimized for CNS applications. Blood brain barrier (BBB) is the main hurdle for CNS drug development. Taking advantage of high throughput virtual screening, we identified a novel and patentable pharmacophore for sEHIs, which is different from previous urea- or amide-based sEHIs.
Through further medicinal chemistry optimization, we developed a lead compound with potent inhibitory activity against sEH in both enzyme and cell-based assays. The lead compound attenuates the inflammatory response in LPS-stimulated primary astrocytes, shows ideal in vivo PK, oral bioavailability and CNS penetration, and reduces LPS-induced neuroinflammation in vivo. A provisional patent covering this novel class of sEH inhibitors has been filed. We are also awarded a U01 grant from NIH/NIA to support a comprehensive medicinal chemistry campaign and all the pre-Investigation New Drug (IND) studies. Successful accomplishment of this project will open a new avenue for treating and preventing AD and advance our scientific knowledge of multiple mechanisms of AD.