TPPU, a Selective and Potent Dual Inhibitor of Soluble Epoxide Hydrolase and p38 Kinase Intervenes in Alzheimer’s Signaling in Human Nerve Cells

Alzheimer’s disease (AD) is the most common neurodegenerative disorder. Neuroinflammation is a prevalent pathogenic stress leading to neuronal death in AD. Targeting neuroinflammation to keep neurons alive is an attractive strategy for AD therapy. 1-Trifluoromethoxyphenyl-3-(1-propionylpiperidin-4-yl) urea (TPPU) is a potent inhibitor of soluble epoxide hydrolase (sEH) and can enter into the brain. It has good efficacy on a wide range of chronic inflammatory diseases in preclinical animal models. However, the anti-neuroinflammatory effects and molecular mechanisms of TPPU for potential AD interventions remain elusive. With an aim to develop multitarget therapeutics for neurodegenerative diseases, we screened TPPU against sEH from different mammalian species and a broad panel of human kinases in vitro for potential new targets relevant to neuroinflammation in AD. TPPU inhibits both human sEH and p38β kinase, two key regulators of inflammation, with nanomolar potencies and distinct selectivity. To further e...