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.