Discovery of memantyl urea derivatives as potent soluble epoxide hydrolase inhibitors against lipopolysaccharide-induced sepsis

Du, Fangyu; Sun, Wenjiao; Morisseau, Christophe; Hammock, Bruce D.; Bao, Xiaoyi; Qiu, Liu; Wang, Chao; Zhang, Tan; Yang, Hao; Zhou, Jun; Xiao, Wei; Liu, Zhongbo; Chen, Guoliang

doi:10.1016/j.ejmech.2021.113678

Cited by 10 publications

(13 citation statements)

References 33 publications

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“…These results suggested that EETs are potentially beneficial under systemic infectious conditions due to their pro-phagocytic ability and anti-inflammatory property. The in vitro studies confirmed that the sEH inhibition prolonged the median survival time and reduced the mortality in septic mice induced by LPS treatment and cecum ligation and puncture (CLP) surgery, respectively [115,117]. Consistent with the sEH inhibitor, COX-2/sEH dual inhibitor PTUPB inhibited inflammatory storm and oxidative stress by increasing HO-1 in the CLP model [118] (Figure 5).…”

Section: The Anti-inflammatory Effects Of Eets In Systemic Infectious...mentioning

confidence: 56%

CYP450 Epoxygenase Metabolites, Epoxyeicosatrienoic Acids, as Novel Anti-Inflammatory Mediators

Shi¹,

Wang

2022

Molecules

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Inflammation plays a crucial role in the initiation and development of a wide range of systemic illnesses. Epoxyeicosatrienoic acids (EETs) are derived from arachidonic acid (AA) metabolized by CYP450 epoxygenase (CYP450) and are subsequently hydrolyzed by soluble epoxide hydrolase (sEH) to dihydroxyeicosatrienoic acids (DHETs), which are merely biologically active. EETs possess a wide range of established protective effects on many systems of which anti-inflammatory actions have gained great interest. EETs attenuate vascular inflammation and remodeling by inhibiting activation of endothelial cells and reducing cross-talk between inflammatory cells and blood vessels. EETs also process direct and indirect anti-inflammatory properties in the myocardium and therefore alleviate inflammatory cardiomyopathy and cardiac remodeling. Moreover, emerging studies show the substantial roles of EETs in relieving inflammation under other pathophysiological environments, such as diabetes, sepsis, lung injuries, neurodegenerative disease, hepatic diseases, kidney injury, and arthritis. Furthermore, pharmacological manipulations of the AA-CYP450-EETs-sEH pathway have demonstrated a contribution to the alleviation of numerous inflammatory diseases, which highlight a therapeutic potential of drugs targeting this pathway. This review summarizes the progress of AA-CYP450-EETs-sEH pathway in regulation of inflammation under different pathological conditions and discusses the existing challenges and future direction of this research field.

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Section: The Anti-inflammatory Effects Of Eets In Systemic Infectious...mentioning

confidence: 56%

CYP450 Epoxygenase Metabolites, Epoxyeicosatrienoic Acids, as Novel Anti-Inflammatory Mediators

Shi¹,

Wang

2022

Molecules

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“…Based on previous explorations made in our laboratory on sEH inhibitors, we chose compound A as the lead compound (Scheme ). , The memantine part and the introduction of a fluorine atom at the 2-position of the benzene ring retard the metabolism of compound A , and it has been demonstrated that the fluorine atom breaks the structural symmetry, lowers the melting point, and increases the solubility of the compound. , The protein code of sEH used for docking is 3WKE, and the eutectic molecule is t -AUCB. The structure of t -AUCB is very similar to that of compound A , both of which have a urea segment and a carboxylic acid segment, so compound A was selected as the basis for docking.…”

Section: Resultsmentioning

confidence: 99%

“…Based on previous explorations made in our laboratory on sEH inhibitors, we chose compound A as the lead compound (Scheme 1). 38,39 The memantine part and the introduction of a fluorine atom at the 2-position of the benzene ring retard the metabolism of compound A, and it has been demonstrated that the fluorine atom breaks the structural symmetry, lowers the melting point, and increases the solubility of the compound. 38,39 The protein code of sEH used for docking is 3WKE, and the eutectic molecule is t-AUCB.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

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Structure-Directed Discovery of Potent Soluble Epoxide Hydrolase Inhibitors for the Treatment of Inflammatory Diseases

Chen

et al. 2023

J. Med. Chem.

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Soluble epoxide hydrolase (sEH) has been identified as an attractive target for anti-inflammatory drug design in recent years. Picomolar level compound G1 against sEH was obtained by introducing the hydrophilic group homopiperazine and hydrophobic fragment propionyl onto the structure of lead compound A. G1 showed good microsomal stability, a moderate plasma protein binding rate, and good oral bioavailability and was well tolerated in rats. G1 has significant analgesic effects on CFA-induced AIA mice, ameliorated the pancreatic injury in acute pancreatitis induced by l-arginine, reversed pancreatic injury, edema, and neutrophil infiltration, and increased the survival time of C57BL/6 mice in a lipopolysaccharide (LPS)-induced sepsis model. Moreover the expression levels of sEH, COX-2, NOS-2, vascular cell adhesion molecule (VCAM), IL-6, MCP-5, and tumor necrosis factor α (TNF-α) were measured by Western blot or enzyme-linked immunosorbent assay (ELISA), with varying degrees of decrease. These results suggested that G1 is a drug candidate worthy of further evaluation for the treatment of inflammation-induced diseases such as arthritis, acute pancreatitis, and sepsis.

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“…Epoxyeicosanoids are generated from PUFAs via the cytochrome P450 (CYP) epoxygenase pathway and are rapidly further metabolized to inactive or even toxic vicinal diols by the soluble epoxide hydrolase (sEH) (10)(11)(12). A series of preclinical studies revealed that transgenic overexpression of CYP epoxygenases as well as genetic or pharmacological sEH inhibition attenuate systemic inflammation and multi-organ damage resulting in reduced mortality in mouse models of lipopolysaccharide (LPS)-induced sepsis (13)(14)(15)(16). N-3 PUFAsupplementation may also synergize with sEH inhibition to suppress inflammation as shown in a variety of other models (17).…”

Section: Introductionmentioning

confidence: 99%

Amelioration of Endotoxemia by a Synthetic Analog of Omega-3 Epoxyeicosanoids

et al. 2022

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Sepsis, a systemic inflammatory response to pathogenic factors, is a difficult to treat life-threatening condition associated with cytokine and eicosanoid storms and multi-organ damage. Omega-3 polyunsaturated fatty acids, such as eicosapentaenoic (EPA) and docosahexaenoic acid, are the precursors of potent anti-inflammatory lipid mediators, including 17,18-epoxyeicosatetraenoic acid (17,18-EEQ), the main metabolite of EPA generated by cytochrome P450 epoxygenases. Searching for novel therapeutic or preventative agents in sepsis, we tested a metabolically robust synthetic analog of 17,18-EEQ (EEQ-A) for its ability to reduce mortality, organ damage, and pro-inflammatory cytokine transcript level in a mouse model of lipopolysaccharide (LPS)-induced endotoxemia, which is closely related to sepsis. Overall survival significantly improved following preventative EEQ-A administration along with decreased transcript level of pro-inflammatory cytokines. On the other hand, the therapeutic protocol was effective in improving survival at 48 hours but insignificant at 72 hours. Histopathological analyses showed significant reductions in hemorrhagic and necrotic damage and infiltration in the liver. In vitro studies with THP-1 and U937 cells showed EEQ-A mediated repression of LPS-induced M1 polarization and enhancement of IL-4-induced M2 polarization of macrophages. Moreover, EEQ-A attenuated the LPS-induced decline of mitochondrial function in THP-1 cells, as indicated by increased basal respiration and ATP production as well as reduction of the metabolic shift to glycolysis. Taken together, these data demonstrate that EEQ-A has potent anti-inflammatory and immunomodulatory properties that may support therapeutic strategies for ameliorating the endotoxemia.

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Discovery of memantyl urea derivatives as potent soluble epoxide hydrolase inhibitors against lipopolysaccharide-induced sepsis

Cited by 10 publications

References 33 publications

CYP450 Epoxygenase Metabolites, Epoxyeicosatrienoic Acids, as Novel Anti-Inflammatory Mediators

CYP450 Epoxygenase Metabolites, Epoxyeicosatrienoic Acids, as Novel Anti-Inflammatory Mediators

Structure-Directed Discovery of Potent Soluble Epoxide Hydrolase Inhibitors for the Treatment of Inflammatory Diseases

Amelioration of Endotoxemia by a Synthetic Analog of Omega-3 Epoxyeicosanoids

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