Discovery of enantioselectivity of urea inhibitors of soluble epoxide hydrolase

Manickam, Manoj; Pillaiyar, Thanigaimalai; Boggu, Pulla Reddy; Venkateswararao, Eeda; Kim, Nam Doo; Lee, Seul Ki; Jeon, Jang Su; Kim, Sang Kyum; Jung, Sang‐Hun

doi:10.1016/j.ejmech.2016.04.015

Cited by 12 publications

(8 citation statements)

References 32 publications

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“…CYP enzymes can metabolize AA to produce four regioisomers, and each isomer has different proportions of S / R - or R / S -enantiomers (Figure ). Because the production rate and ratio of stereoisomers of these diol products are closely related to the stereochemistry of substrates and epoxy ring substitution, stereoselectivity is also an important factor in the design of sEH inhibitors . Manickam et al designed a series of pairs of enantiomers with a chiral center close to urea nitrogen atoms .…”

Section: Seh Inhibitorsmentioning

confidence: 99%

Discovery of Soluble Epoxide Hydrolase Inhibitors from Chemical Synthesis and Natural Products

et al. 2020

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Soluble epoxide hydrolase (sEH) is an α/β hydrolase fold protein and widely distributed in numerous organs including the liver, kidney, and brain. The inhibition of sEH can effectively maintain endogenous epoxyeicosatrienoic acids (EETs) levels and reduce dihydroxyeicosatrienoic acids (DHETs) levels, resulting in therapeutic potentials for cardiovascular, central nervous system, and metabolic diseases. Therefore, since the beginning of this century, the development of sEH inhibitors is a hot research topic. A variety of potent sEH inhibitors have been developed by chemical synthesis or isolated from natural sources. In this review, we mainly summarized the interconnected aspects of sEH with cardiovascular, central nervous system, and metabolic diseases and then focus on representative inhibitors, which would provide some useful guidance for the future development of potential sEH inhibitors.

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Section: Seh Inhibitorsmentioning

confidence: 99%

Discovery of Soluble Epoxide Hydrolase Inhibitors from Chemical Synthesis and Natural Products

et al. 2020

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“…Most of compounds reported as sEH inhibitors are 1,3-disubstituted ureas. 11–15 To our knowledge, only 10 thioureas have been reported as sEH inhibitors 16,17 compared to thousands of ureas. Thus, a systematic investigation of thioureas as sEH inhibitors is needed.…”

mentioning

confidence: 99%

Adamantyl thioureas as soluble epoxide hydrolase inhibitors

Burmistrov

Morisseau

Pitushkin

et al. 2018

Bioorganic & Medicinal Chemistry Letters

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A series of inhibitors of the soluble epoxide hydrolase (sEH) containing one or two thiourea groups has been developed. Inhibition potency of the described compounds ranges from 50 μM to 7.2 nM. 1,7-(Heptamethylene)bis[(adamant-1-yl)thiourea] (6f) was found to be the most potent sEH inhibitor, among the thioureas tested. The inhibitory activity of the thioureas against the human sEH is closer to the value of activity against rat sEH rather than murine sEH. While being less active, thioureas are up to 7-fold more soluble than ureas, which makes them more bioavailable and thus promising as sEH inhibitors.

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“…Figure 2A shows that they inhibit sEH activity in a dose-dependent manner at concentrations of ~1-30 µg/mL. To calculate the half maximal inhibitory concentration of inhibitors (IC50), these inhibition rate values were fitted by Equation (2). Inhibitors 1-3 were found to have IC50 values of 11.6±2.9, 14.4±1.5, and 42.7±3.5 µg/mL, respectively (Table 1).…”

Section: Isolation Identification and Enzyme Assaymentioning

confidence: 99%

“…EETs exist as four regioisomeric metabolites; 5,6-, 8,9-, 11,12-and 14,15-EETs [1]. Furthermore, soluble epoxide hydrolase (sEH, E.C.3.3.2.10) biosynthesizes dihydroxyeicosatrienic acids (DHETs) from EETs by hydrolyzing the epoxide ring of EETs into a diol [2]. Since EETs were revealed as endothelium-derived hyperpolarizing factors in 1996, they have been found to have biologicalactivities, such as anti-inflammatory, anti-hypertensive, kidney-protective, and cardiac-protective effects [3].…”

Section: Introductionmentioning

confidence: 99%

Inhibitory Activity of Flavonoids, Chrysoeriol and Luteolin-7-O-Glucopyranoside, on Soluble Epoxide Hydrolase from Capsicum chinense

Kim

Jin

2020

Biomolecules

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Three flavonoids derived from the leaves of Capsicum chinense Jacq. were identified as chrysoeriol (1), luteolin-7-O-glucopyranoside (2), and isorhamnetin-7-O-glucopyranoside (3). They had IC50 values of 11.6±2.9, 14.4±1.5, and 42.7±3.5 µg/mL against soluble epoxide hydrolase (sEH), respectively. The three inhibitors (1–3) were found to non-competitively bind into the allosteric site of the enzyme with Ki values of 10.5 ± 3.2, 11.9 ± 2.8 and 38.0 ± 4.1 µg/mL, respectively. The potential inhibitors 1 and 2 were located at the left edge ofa U-tube shape that contained the enzyme active site. Additionally, we observed changes in several factors involved in the binding of these complexes under 300 K and 1 bar. Finally, it was confirmed that each inhibitor, 1 and 2, could be complexed with sEH by the “induced fit” and “lock-and-key” models.

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Discovery of enantioselectivity of urea inhibitors of soluble epoxide hydrolase

Cited by 12 publications

References 32 publications

Discovery of Soluble Epoxide Hydrolase Inhibitors from Chemical Synthesis and Natural Products

Discovery of Soluble Epoxide Hydrolase Inhibitors from Chemical Synthesis and Natural Products

Adamantyl thioureas as soluble epoxide hydrolase inhibitors

Inhibitory Activity of Flavonoids, Chrysoeriol and Luteolin-7-O-Glucopyranoside, on Soluble Epoxide Hydrolase from Capsicum chinense

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