Synthesis, Docking Study and Biological Evaluation of Amide-Based Soluble Epoxide Hydrolase Inhibitors with Novel Secondary Pharmacophore of Pyrimidin-2-ol.

Soluble epoxide hydrolase enzyme (sEH) is one of the most promising and emerging targets to develop drugs for multiple disease indications, including hypertension, diabetes, stroke, dyslipidemia, pain, etc. Most inhibitor scaffolds have a urea or amide moiety to mimic the active-site transition state. In this regard, we developed a series of amide sEH inhibitors with a pyrimidin-2-ol ring as a new secondary pharmacophore, which was subjected to in vitro evaluation. Compound 4w (4-chloro-N-{4-[6-(4-chlorophenyl)-2-hydroxypyrimidin-4-yl]phenyl}benzamide), which contains 4-chloro substituent in both terminal phenyl rings, exhibited the most inhibitory activity against sEH with an IC50 value of 1.2 nM. Molecular docking analysis of the synthesized compounds revealed that the greater number of hydrogen bonding interactions of the amide group as the primary pharmacophore with Asp-353, Tyr-383, and Tyr-466 as the key catalytic residue triad of the enzyme played a critical role and led to a more favorable binding affinity. Pharmacokinetic properties of the synthesized compounds were calculated in silico, and all ADMET indices fell within acceptable ranges. Altogether, the results of this work could provide useful information on 4,6-diphenylpyrimidin-2-olas sEH inhibitors which can be utilized in further development in this area.