Substituted phenyl groups improve the pharmacokinetic profile of urea‐based soluble epoxide hydrolase inhibitors

Abstract

Soluble epoxide hydrolase inhibitors (sEHIs) are anti‐inflammatory, analgesic, anti‐hypertensive, cardio‐protective and renal‐protective in multiple animal models. However, the earlier adamantyl urea‐based inhibitors are metabolically susceptible which limits their pharmacological use. Therefore, novel potent inhibitors with the replacement of an adamantyl group by a substituted phenyl group are synthesized to presumptively offer better pharmacokinetic (PK) properties including metabolic stability. Here we present the PK profiles of new inhibitors in a murine model. The PK profiles of sEHIs were determined following p.o. administration and serial bleeding in mice. The blood levels of inhibitors were measured by a HPLC/MS/MS method. Compared with the earlier adamantyl urea‐based inhibitors, substituted phenyl urea‐based inhibitors afford more favorable PK properties, such as higher Cmaxs, higher AUCs and longer t1/2s, which, as expected, show more stable metabolic stability. The sEHIs with substituted phenyl group are more metabolically stable than those with adamantly group. This indicates a new strategy for development of sEHIs for further study toward clinical trials.