1-Aryl-3-(1-acylpiperidin-4-yl)urea Inhibitors of Human and Murine Soluble Epoxide Hydrolase: Structure−Activity Relationships, Pharmacokinetics, and Reduction of Inflammatory Pain

Rose, Tristan E.; Morisseau, Christophe; Liu, Jun-Yan; Inceoglu, Bora; Jones, Paul D.; Sanborn, James R.; Hammock, Bruce D.

doi:10.1021/jm100691c

Cited by 146 publications

(216 citation statements)

References 49 publications

Supporting

Mentioning

209

Contrasting

Order By: Relevance

“…3-(1-propionylpiperidine-4-yl)urea (TPPU: a potent sEH inhibitor) (31)(32)(33) and the endogenous eicosanoid 14,15-EET on nerve growth factor (NGF)-induced neurite outgrowth in PC12 cells. Both TPPU and 14,15-EET potentiated NGF-induced neurite outgrowth in PC12 cells, in a concentration-dependent manner (Fig.…”

Section: Significancementioning

confidence: 99%

Gene deficiency and pharmacological inhibition of soluble epoxide hydrolase confers resilience to repeated social defeat stress

Ren

Ishima

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

127

149

View full text Add to dashboard Cite

Depression is a severe and chronic psychiatric disease, affecting 350 million subjects worldwide. Although multiple antidepressants have been used in the treatment of depressive symptoms, their beneficial effects are limited. The soluble epoxide hydrolase (sEH) plays a key role in the inflammation that is involved in depression. Thus, we examined here the role of sEH in depression. In both inflammation and social defeat stress models of depression, a potent sEH inhibitor, TPPU, displayed rapid antidepressant effects. Expression of sEH protein in the brain from chronically stressed (susceptible) mice was higher than of control mice. Furthermore, expression of sEH protein in postmortem brain samples of patients with psychiatric diseases, including depression, bipolar disorder, and schizophrenia, was higher than controls. This finding suggests that increased sEH levels might be involved in the pathogenesis of certain psychiatric diseases. In support of this hypothesis, pretreatment with TPPU prevented the onset of depression-like behaviors after inflammation or repeated social defeat stress. Moreover, sEH KO mice did not show depressionlike behavior after repeated social defeat stress, suggesting stress resilience. The sEH KO mice showed increased brain-derived neurotrophic factor (BDNF) and phosphorylation of its receptor TrkB in the prefrontal cortex, hippocampus, but not nucleus accumbens, suggesting that increased BDNF-TrkB signaling in the prefrontal cortex and hippocampus confer stress resilience. All of these findings suggest that sEH plays a key role in the pathophysiology of depression, and that epoxy fatty acids, their mimics, as well as sEH inhibitors could be potential therapeutic or prophylactic drugs for depression.brain-derived neurotrophic factor | depression | epoxyeicosatrienoic acid | soluble epoxide hydrolase | resilience

show abstract

Section: Significancementioning

confidence: 99%

Gene deficiency and pharmacological inhibition of soluble epoxide hydrolase confers resilience to repeated social defeat stress

Ren

Ishima

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

127

149

View full text Add to dashboard Cite

show abstract

“…Human sEH (1 nM) was Previous studies on urea-based inhibitors containing piperidine moiety have shown that the hydrophobic cycloalkyl groups on the left-hand side of the molecules are positively correlated with inhibitory potency. 17 Among this set of analogs we identified several inhibitors possessing improved or similar potency comparing to the lead compound 2, specifically compound 7-10 showed an IC 50 of 0.4 nM, the most potent amide non-urea sEH inhibitor reported to date. Replacement of cycloalkyl ring with a more compact phenyl ring (compound 7-12), resulted in 15-fold drop in potency against the human sEH.…”

Section: Nih Public Accessmentioning

confidence: 99%

“…16 Herein we report modifications of the left-hand side of non-urea inhibitor 2. In particular, we were focused on the replacement of the cycloheptyl moiety of the 2, following the SAR reported by Rose et al 17 , and guided by docking model of the previously reported proteininhibitor complex and X-ray cocrystal structure of human sEH and 1.The X-ray crystallographic structure of human sEH and an inhibitor 4-(3-cyclohexylureido)-carboxylic acid complex (PDB code: 1ZD3) revealed the catalytic pocket and key structural features required to inhibit sEH enzyme. Two tyrosine (Tyr383 and Tyr466) and one aspartic acid (Asp335) residues, located in the hydrolase catalytic pocket of sEH, are involved in degradation of EET -tyrosine residues act as hydrogen bond donors to promote the epoxide ring opening by Asp335.…”

mentioning

confidence: 99%

mentioning

confidence: 99%

“…17 Among this set of analogs we identified several inhibitors possessing improved or similar potency comparing to the lead compound 2, specifically compound 7-10 showed an IC 50 of 0.4 nM, the most potent amide non-urea sEH inhibitor reported to date. Replacement of cycloalkyl ring with a more compact phenyl ring (compound 7-12), resulted in 15-fold drop in potency against the human sEH.…”

mentioning

confidence: 99%

See 2 more Smart Citations

Synthesis and structure–activity relationship of piperidine-derived non-urea soluble epoxide hydrolase inhibitors

Pecic¹,

Pakhomova²,

Newcomer³

et al. 2013

Bioorganic & Medicinal Chemistry Letters

Self Cite

View full text Add to dashboard Cite

A series of potent amide non-urea inhibitors of soluble epoxide hydrolase (sEH) is disclosed. The inhibition of soluble epoxide hydrolase leads to elevated levels of epoxyeicosatrienoic acids (EETs), and thus inhibitors of sEH represent one of a novel approach to the development of vasodilatory and anti-inflammatory drugs. Structure-activities studies guided optimization of a lead compound, identified through high-throughput screening, gave rise to sub-nanomolar inhibitors of human sEH with stability in human liver microsomal assay suitable for preclinical development. KeywordsSoluble epoxide hydrolase; Non-urea inhibitors; Hypertension; Human liver microsomes stability Soluble epoxide hydrolase (sEH) is a bifunctional homodimeric enzyme with hydrolase and phosphatase activity detected in various species ranging from plants to mammals. 1 In humans it is mostly located in liver, kidney, intestinal and vascular tissues. 2 The sEH enzyme is selective for aliphatic epoxides of fatty acids, and one of the most important substrates is epoxyeicosatrienoic acid (EET). 3 EETs are one of the metabolic derivatives of arachidonic acid. 4 The epoxygenase CYP2 enzymes catalyse the epoxydation of olefin bonds of arachidonic acid generating EETs. 5 EETs exhibit vasodilatory effects in various arteries 6,7 and possess anti-inflammatory properties. 8 sEH mediates the addition of water to EETs, converting them to the corresponding diols -dihydroxyeicosatrienoic acids (DHETs), which show abolished or diminished biological activity . The inhibition of this enzyme, therefore may represent a promising therapeutic strategy since it would lead to elevated levels of EETs, which could then have beneficial therapeutic effects on blood pressure and inflammation. 9 * Corresponding author. Tel.: +1-212-305-1152; fax: +1-212-305-3475; sd184@columbia.edu (Shixian Deng) .Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. The most explored sEH inhibitors to date are urea-based compounds and numerous structure-activity relationship (SAR) studies led to discovery of several potent urea-based sEH inhibitors with IC 50 s in the lower nanomolar range. 10,11 However, the urea-based inhibitors often suffer from poor solubility and stability, which hinders their pharmacological use in vivo. 12,13 Amides, carbamates and thioureas have been evaluated as alternative pharmacophores in an attempt to improve physical properties of urea-based inhibitors. 10,11 In this report we disclose our efforts towards designing novel non-urea, amide-based inhibitors of sEH. NIH Public AccessPreviously we identified through high...

show abstract

Extrahepatic Drug‐Metabolizing Enzymes and Their Significance

Jhajra

Varkhede

Ahire

et al. 2012

Encyclopedia of Drug Metabolism and Interactions

View full text Add to dashboard Cite

Drug‐metabolizing enzymes (DMEs) are primarily expressed in the liver but their role in the extrahepatic tissues such as gastrointestinal tract (GIT), pulmonary, excretory, nervous, cardiovascular system, and skin cannot be neglected. Generally, the expression of DMEs in extrahepatic tissues is quantitatively lower than that in the liver, but there are a few enzymes such as CYP1A1, CYP1B1, CYP2F1, and CYP2U1 that are more abundant in extrahepatic organs. As many extrahepatic organs are portals for administered drugs, DMEs expressed in these organs can be responsible for significant metabolism, leading to first‐pass effects and lower bioavailability. Extrahepatic DMEs are also involved in bioactivation of prodrugs and formation of reactive metabolites that may interact with cellular components, resulting in organ‐specific toxicity. Activity and expression of extrahepatic DMEs is often altered by coadministered drugs, leading to drug–drug interactions. Expression of DMEs in living beings affected by a host of environmental and genetic factors such as genetic polymorphism, age, gender, pathophysiological conditions, inborn errors in metabolism, food habits, and environmental pollutants, contributing to varied drug effects and idiosyncratic toxicities.

show abstract

1-Aryl-3-(1-acylpiperidin-4-yl)urea Inhibitors of Human and Murine Soluble Epoxide Hydrolase: Structure−Activity Relationships, Pharmacokinetics, and Reduction of Inflammatory Pain

Cited by 146 publications

References 49 publications

Gene deficiency and pharmacological inhibition of soluble epoxide hydrolase confers resilience to repeated social defeat stress

Gene deficiency and pharmacological inhibition of soluble epoxide hydrolase confers resilience to repeated social defeat stress

Synthesis and structure–activity relationship of piperidine-derived non-urea soluble epoxide hydrolase inhibitors

Extrahepatic Drug‐Metabolizing Enzymes and Their Significance

Contact Info

Product

Resources

About