Discovery of enantioselectivity of urea inhibitors of soluble epoxide hydrolase.

Abstract

Soluble epoxide hydrolase (sEH) hydrolyzes epoxyeicosatrienoic acids (EETs) in the metabolic pathway of arachidonic acid and has been considered as an important therapeutic target for chronic diseases such as hypertension, diabetes and inflammation. Although many urea derivatives are known as sEH inhibitors, the enantioselectivity of the inhibitors is not highlighted in spite of the stereoselective hydrolysis of EETs by sEH. In an effort to explore the importance of enantioselectivity in the urea scaffold, a series of enantiomers with the stereocenter adjacent to the urea nitrogen atom were prepared. The selectivity of enantiomers of 1-(α-alkyl-α-phenylmethyl)-3-(3-phenylpropyl)ureas showed wide range differences up to 125 fold with the low IC50 value up to 13 nM. The S-configuration with planar phenyl and small alkyl groups at α-position is crucial for the activity and selectivity. However, restriction of the free rotation of two α-groups with indan-1-yl or 1,2,3,4-tetrahydronaphthalen-1-yl moiety abolishes the selectivity between the enantiomers, despite the increase in activity up to 13 nM. The hydrophilic group like sulfonamido group at para position of 3-phenylpropyl motif of 1-(α-alkyl-α-phenylmethyl-3-(3-phenylpropyl)urea improves the activity as well as enantiomeric selectivity. All these ureas are proved to be specific inhibitor of sEH without inhibition against mEH.

• Authors: Manoj Manickam, Thanigaimalai Pillaiyar, PullaReddy Boggu, Eeda Venkateswararao, Hitesh B Jalani, Nam-Doo Kim, Seul Ki Lee, Jang Su Jeon, Sang Kyum Kim, Sang-Hun Jung
• Journal: European journal of medicinal chemistry (Eur J Med Chem) Vol. 117 Pg. 113-24 (Jul 19 2016) ISSN: 1768-3254 [Electronic] France
• PMID: 27092411 (Publication Type: Journal Article)
• Copyright: Copyright © 2016. Published by Elsevier Masson SAS.

Chemical References

• Enzyme Inhibitors
• Urea
• Epoxide Hydrolases

Topics

• Chronic Disease (drug therapy)
• Drug Discovery
• Enzyme Inhibitors (chemical synthesis)
• Epoxide Hydrolases (antagonists & inhibitors)
• Humans
• Isomerism
• Solubility
• Stereoisomerism
• Urea (analogs & derivatives)