Discovery of Orally Active Phenylquinoline-Based Soluble Epoxide Hydrolase Inhibitors with Anti-Inflammatory and Analgesic Activity

Currently, there are no specific drugs for treating acute
pancreatitis.
Soluble epoxide hydrolase (sEH) inhibitors show promise, but face
challenges like low blood drug concentrations and potential adverse
effects on CYP enzymes and the human ether-a-go-go-related gene (hERG).
In this study, an approach involving scaffold hopping and structure–activity
guided optimization was employed to design a series of phenylquinoline-based
sEH inhibitors. Among these compounds, DJ-53 exhibited
potent in vitro and in vivo effects
in alleviating pain and reducing inflammation. The in vivo mechanism of action involved inhibiting sEH enzyme activity, thereby
increasing levels of anti-inflammatory epoxyeicosatrienoic acids (EETs)
and decreasing levels of proinflammatory dihydroxyeicosatrienoic acids
(DHETs). Importantly, DJ-53 showed exceptional oral bioavailability
and pharmacokinetics, while avoiding inhibition of CYP enzymes or
the hERG channel. These results highlight DJ-53′s potential
as a new lead compound for anti-inflammatory and analgesic applications
and provide a safe and effective scaffold for developing sEH inhibitors.