Soluble epoxide hydrolase (sEH) is an enzyme that catalyzes the conversion of epoxyeicosatrienoic acids (EETs) into dihydroxy eicosatrienoic acids (DHETs). EETs show physiologically beneficial effects such as vasodilatation, vasoprotection, and anti-inflammation. sEH inhibition exhibits the effects expected from an increase in EET level.We identified spirocyclic diamine derivatives as highly potent sEH inhibitors and orally active agents for treating chronic kidney diseases (CKD).  Renal sEH expression is up-regulated in CKD rats. Oral administration of the derivatives at a dose of 30 mg/kg reduced serum creatinine levels in CKD rats. This result suggests that the derivatives are orally active drug candidates for the treatment of CKD. Along with the synthesis of these derivatives, their structure-activity relationships and pharmacological properties are described.

Discovery of novel spirocyclic diamine derivatives as highly potent sEH inhibitors for treating of chronic kidney diseases

247th National Meeting (2014)

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