Development of Potent and Selective Dual PPARδ/sEH Modulators from an AI-Designed Scaffold.

Designed polypharmacology is an evolving concept to achieve improved therapeutic efficacy in multifactorial diseases. Dual soluble epoxide hydrolase (sEH) inhibition and peroxisome proliferator-activated receptor δ (PPARδ) activation hold promise as designed polypharmacology in metabolic dysfunction and associated liver diseases by improving whole-body energy balance, decreasing hepatic inflammation and lipotoxicity, and providing cardiovascular protection. Here we developed dual PPARδ/sEH modulators from a computationally designed lead fusing pharmacophore elements of ligands for both targets. Systematic SAR exploration of the scaffold identified substructures driving PPARδ agonism or sEH inhibition and a combination of favored modifications provided potent dual modulators. The optimized dual ligands displayed balanced activity on both proteins of interest and selectivity over related targets including the PPARα/γ subtypes. Additionally, we identified structurally matched selective modulators of both targets of interest as controls, forming a set of tools to explore the therapeutic potential of PPARδ/sEH-targeted polypharmacology.