The effect of the linker in urea‐based soluble epoxide hydrolase inhibitors’ on their blood‐brain penetration ability and drug‐like properties

Abstract

Soluble epoxide hydrolase (sEH) is a novel therapeutic target for the treatment neurodegenerative diseases, including Parkinson’s disease and Alzheimer’s disease. Although many sEH inhibitors exhibit sub‐nanomolar potency, they suffer from poor blood‐brain barrier penetration and drug‐like properties. As high in vivolevel is required to achieve clinical efficacy for sEH inhibitors for other therapeutic applications, low CNS penetration represents a significant barrier for success for CNS diseases. Therefore, sEH inhibitors with high blood‐brain barrier penetration are needed.Although significant structure‐activity relationships (SAR) have been reported, little data exist exploring the features that overcome the blood‐brain barrier. Most SAR studies have focused on terminal substitutions on both ends of the reported inhibitors with little focus on the “linker” or core of the inhibitors. In this presentation, we will show how the “linker” of urea‐based sEH inhibitors affects their potency, physical properties, and ability to penetrate the blood‐brain barrier. Based on our computational model and the crystal structure of our lead compound, we have prepared new sEH inhibitors with linker containing various ring sizes, bicyclic structures, and simple methyl or fluorine substituents. Perhaps not unexpectantly, the linker of sEH inhibitors has substantial effects on the inhibitor’s potency, solubility, and blood‐brain barrier penetration. In some cases, we observed an increase in blood‐brain penetration by 4‐fold and improvements in solubility by almost 10‐fold. In addition, unexpectedly, our data provides new insights that the linker of the sEH inhibitor affects the binding kinetics without improving the potency of the inhibitors. Our results will create a new direction for the design of novel sEH inhibitors, and we are in the process of leveraging the existing SAR to create much‐improved sEH inhibitors to treat neurodegenerative diseases.