Discovery of enantioselectivity of urea inhibitors of soluble epoxide hydrolase.
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.
College of Pharmacy and Institute of Drug Research and Development, Chungnam National University, Daejeon 34134, South Korea.
Manoj
M
Manickam
College of Pharmacy and Institute of Drug Research and Development, Chungnam National University, Daejeon 34134, South Korea.
Thanigaimalai
T
Pillaiyar
College of Pharmacy and Institute of Drug Research and Development, Chungnam National University, Daejeon 34134, South Korea.
PullaReddy
P
Boggu
College of Pharmacy and Institute of Drug Research and Development, Chungnam National University, Daejeon 34134, South Korea.
Eeda
E
Venkateswararao
College of Pharmacy and Institute of Drug Research and Development, Chungnam National University, Daejeon 34134, South Korea.
Hitesh B
HB
Jalani
DGMIF, New Drug Development Center, 80, Cheombok-ro, Dong-gu, Daegu 41061, South Korea.
Nam-Doo
ND
Kim
College of Pharmacy and Institute of Drug Research and Development, Chungnam National University, Daejeon 34134, South Korea.
Seul Ki
SK
Lee
College of Pharmacy and Institute of Drug Research and Development, Chungnam National University, Daejeon 34134, South Korea.
Jang Su
JS
Jeon
College of Pharmacy and Institute of Drug Research and Development, Chungnam National University, Daejeon 34134, South Korea.
Sang Kyum
SK
Kim
College of Pharmacy and Institute of Drug Research and Development, Chungnam National University, Daejeon 34134, South Korea. Electronic address: jungshh@cnu.ac.kr.
Sang-Hun
SH
Jung
D002908:Chronic Disease / Q000188:drug therapy; D055808:Drug Discovery; D004791:Enzyme Inhibitors / Q000138:chemical synthesis*; D004851:Epoxide Hydrolases / Q000037:antagonists & inhibitors*; D006801:Humans; D007536:Isomerism; D012995:Solubility; D013237:Stereoisomerism; D014508:Urea / Q000031:analogs & derivatives*
D004791:Enzyme Inhibitors; D014508:Urea; D004851:Epoxide Hydrolases
EETs; Enantioselectivity; Inhibitors; Soluble epoxide hydrolase; Urea derivatives