Inhibitors Of Human Soluble Epoxide Hydrolase Research Articles

Quinazoline-4(3H)-one-7-carboxamide Derivatives as Human Soluble Epoxide Hydrolase Inhibitors with Developable 5-Lipoxygenase Activating Protein Inhibition.

Soluble epoxide hydrolase (sEH) metabolizes epoxyeicosatrienoic acids (EETs), which are endowed with beneficial biological activities as they reduce inflammation, regulate endothelial tone, improve mitochondrial function, and decrease oxidative stress. Therefore, inhibition of sEH for maintaining high EET levels is implicated as a new therapeutic modality with broad clinical applications for metabolic, renal, and cardiovascular disorders. In our search for new sEH inhibitors, we designed and synthesized novel amide analogues of the quinazolinone-7-carboxylic acid derivative 5, a previously discovered 5-lipoxygenase-activating protein (FLAP) inhibitor, to evaluate their potential for inhibiting sEH. As a result, we identified new quinazolinone-7-carboxamides that demonstrated selective sEH inhibition with decreased FLAP inhibitor properties. The tractable SAR results indicated that the amide and thiobenzyl fragments flanking the quinazolinone nucleus are critical features governing the potent sEH inhibition, and compounds 34, 35, 37, and 43 inhibited the sEH activity with IC50 values of 0.30–0.66 μM. Compound 34 also inhibited the FLAP-mediated leukotriene biosynthesis (IC50 = 2.91 μM). In conclusion, quinazolinone-7-carboxamides can be regarded as novel lead structures, and newer analogues with improved efficiency against sEH along with or without FLAP inhibition can be generated.

Bioisosteric substitution of adamantane with bicyclic lipophilic groups improves water solubility of human soluble epoxide hydrolase inhibitors

A series of inhibitors of the soluble epoxide hydrolase (sEH) containing lipophilic groups of natural origin (camphanyl, norcamphanyl, furan-2-yl) were developed. Inhibitory potency ranging from 0.4 nM to 2.16 μM were obtained. While having the same level of inhibitory activity bicyclic ureas are up to 10-fold more soluble than the corresponding ureas containing adamantyl or 4-trifluoromethoxyphenyl substituents. This makes them easier to formulate, more bioavailable and thus more promising as therapeutic sEH inhibitors. Endo/exo-form of compound 2b derived from l-camphor is 14-fold more potent than the corresponding analogue derived from d-camphor (IC50 = 3.7 nM vs. 50.6 nM) indicating enantiomeric preference.

Synthesis and Properties of N,N′-Disubstituted Ureas and Their Isosteric Analogs Containing Polycyclic Fragments: II. N-(4-Oxoadamantan-1-yl)-N′-[fluoro(chloro)phenyl]ureas

A series of N-(4-oxoadamantan-1-yl)-N′-[fluoro(chloro)phenyl]ureas have been synthesized in 27–73% yields by reaction of 1-isocyanatoadamantan-4-one with fluoro- and chlorosubstituted anilines. The products are promising as human soluble epoxide hydrolase inhibitors.

Synthesis of Bicyclic Isocyanates and Bioisosteric 1,3-Disubstituted Ureas as Soluble Epoxide Hydrolase Inhibitors

(1S)-1-Isocyanato-4,7,7-trimethyl-2-oxabicyclo[2.2.1]heptan-3-one and 2-isocyanatobicyclo[2.2.1]-hept-5-ene were prepared by the Curtius rearragement reaction from the corresponding carboxylic acids. The synthesized isocyanates were used to synthesize, in high yields of 74–93%, bioisosteric 1,3-disubstituted ureas as potential human soluble epoxide hydrolase inhibitors.

Newly Designed and Improved Human Soluble Epoxide Hydrolase Inhibitors for Neuropathic pain

Soluble epoxide hydrolase (sEH, EC 3.3.2.10) is responsible for metabolism of endogeneously derived fatty acid oxiranes, epoxyeicosatrienoic acids (EETs) to the corresponding diols, dihydroxyepoxyeicosatrienoic acids (DHETs). EETs are the products of arachidonic acid by cytochromes P450 epoxygenases and are key modulators involved in inflammation, pain and blood pressure. Inhibition of sEH that results in an increase in endogenous EETs, which have a significant effect on resolving inflammation and high blood pressure in rodent models. Therefore, the sEH has emerged as a pharmaceutical target for hypertension, inflammation and organ‐protection. Recently, we have demonstrated that elevation of epoxy‐fatty acid through sEH inhibition is able to resolve diabetic neuropathic pain in rodent.Over last decade, a series of N,N′‐disubstituted ureas has been developed to study the physiological effects of sEH inhibition in various murine and rodent models and their beneficial effects in several animals disease models has been demonstrated. To better study the effect of epoxy‐fatty acids on health, a set of new compounds with dramatically potency, a better solubility and an improved pharmacokinetic profiles has been synthesized, their PK‐ADME and efficacy on diabetic neuropathic pain will be determined and the results will be presented and discussed here.

Advances in the Research of Human Soluble Epoxide Hydrolase Inhibitors

Advances in the Research of Human Soluble Epoxide Hydrolase Inhibitors

Pharmacophoric Modeling and Atom-Based 3D-QSAR of Novel 1-Aryl-3-(1-acylpiperidin-4-yl) Urea as Human Soluble Epoxide Hydrolase Inhibitors (sEHIs)

Soluble Epoxide Hydrolase (sEH) is an important and promising new pharmacologic target for the treatment of acute systemic inflammation. Inhibition of sEH by a highly selective and potent sEH inhibitor (sEHI) elevates the epoxyeicosatrienoic acids (EETs) level in vivo leading to decreased inflammation. To explore the necessary structural requirement of 1, 3-disubstituted ureas as sEH inhibitors for anti-inflammatory activity, the molecular modeling studies have been pursued. A ligand-based pharmacophoric model and atom-based 3D-QSAR have been generated by Phase. Binding interaction as determined by the docking study revealed that these inhibitors interact at active site (ASP 335 & TYR 383) of sEH enzyme. The pharmacophore model was further used as a 3D query for virtual screening to retrieve potential inhibitors.