Structure-Based Design of Dual Partial Peroxisome Proliferator-Activated Receptor γ Agonists/Soluble Epoxide Hydrolase Inhibitors

Polypharmaceutical regimens often
impair treatment of patients
with metabolic syndrome (MetS), a complex disease cluster, including
obesity, hypertension, heart disease, and type II diabetes. Simultaneous
targeting of soluble epoxide hydrolase (sEH) and peroxisome proliferator-activated
receptor γ (PPARγ) synergistically counteracted MetS in
various in vivo models, and dual sEH inhibitors/PPARγ
agonists hold great potential to reduce the problems associated with
polypharmacy in the context of MetS. However, full activation of PPARγ
leads to fluid retention associated with edema and weight gain, while
partial PPARγ agonists do not have these drawbacks. In this
study, we designed a dual partial PPARγ agonist/sEH inhibitor
using a structure-guided approach. Exhaustive structure–activity
relationship studies lead to the successful optimization of the designed
lead. Crystal structures of one representative compound with both
targets revealed potential points for optimization. The optimized
compounds exhibited favorable metabolic stability, toxicity, selectivity,
and desirable activity in adipocytes and macrophages.