Mining biologically-active molecules for inhibitors of fatty acid amide hydrolase (FAAH): Identification of phenmedipham and amperozide as FAAH inhibitors

Vincent, Fabien; Nguyen, Margaret; Emerling, Daniel; Kelly, Michael G.; Duncton, Matthew A. J.

doi:10.1016/j.bmcl.2009.09.086

Cited by 9 publications

(2 citation statements)

References 41 publications

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“…So far,t he urea SMP-028 [83] has been described asaselective inhibitor of the hormone-sensitive CEase from different species (rat, IC 50 = 1.01 mm;m onkey, IC 50 = 31.1 mm;h uman, IC 50 = 33.8 mm), [83] whereas no phthalimide-containing compound decreases CEase's activity.T he same applies for MAGL and FAAH, in which (several) ureas but no phthalimide derivativeh ave been characterized as inhibitors yet. [84][85][86][87][88] In this context, various MAGL and FAAH inhibitors bearingp iperidinyl, piperazinyl,a zetidinyl, triazole,a nd triazolopyridine urea scaffolds have been developed by several pharmaceutical companies, causing (selective or "dual") irreversible inactivation of these two enzymes. [44,[89][90][91]…”

Section: Characterizationo Fw-phthalimidoalkyl Aryl Ureas As Inhibitomentioning

confidence: 99%

ω‐Phthalimidoalkyl Aryl Ureas as Potent and Selective Inhibitors of Cholesterol Esterase

et al. 2018

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Cholesterol esterase (CEase), a serine hydrolase thought to be involved in atherogenesis and thus coronary heart disease, is considered as a target for inhibitor development. We investigated recombinant human and murine CEases with a new fluorometric assay in a structure-activity relationship study of a small library of ω-phthalimidoalkyl aryl ureas. The urea motif with an attached 3,5-bis(trifluoromethyl)phenyl group and the aromatic character of the ω-phthalimide residue were most important for inhibitory activity. In addition, an alkyl chain composed of three or four methylene groups, connecting the urea and phthalimide moieties, was found to be an optimal spacer for inhibitors. The so-optimized compounds 2 [1-(3,5-bis(trifluoromethyl)phenyl)-3-(3-(1,3-dioxoisoindolin-2-yl)propyl)urea] and 21 [1-(3,5-bis(trifluoromethyl)phenyl)-3-(4-(1,3-dioxoisoindolin-2-yl)butyl)urea] exhibited dissociation constants (K ) of 1-19 μm on the two CEases and showed either a competitive (2 on the human enzyme and 21 on the murine enzyme) or a noncompetitive mode of inhibition. Two related serine hydrolases-monoacylglycerol lipase and fatty acid amide hydrolase-were inhibited by ω-phthalimidoalkyl aryl ureas to a lesser extent.

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Section: Characterizationo Fw-phthalimidoalkyl Aryl Ureas As Inhibitomentioning

confidence: 99%

ω‐Phthalimidoalkyl Aryl Ureas as Potent and Selective Inhibitors of Cholesterol Esterase

et al. 2018

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“…Only one compound ZINC19632922 showed an increase in RMSD (see Table 2) which can be due to benzo-furan group solvent exposure (see Figure 5). This compound is a drug known as Befuraline, it was previously reported as inhibitor of Proteinase-activated receptor 1, and Anandamide amidohydrolase (Planty et al 2010;Vincent et al 2009).…”

Section: Discussionmentioning

confidence: 99%

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Supplemental Information 1: Docking Score and Reanking for Selected Molecules

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Background: Arterial thrombosis causes heart attacks and strokes and constitutes one of the leading causes of morbidity and mortality in the world and few therapies are available for its treatment. Thus, new therapeutic approaches in the prevention and treatment of arterial thrombosis are needed. Protein disulfide isomerase (PDI) has been shown to be expressed on vascular cells following injury and to be involved in regulating thrombus formation in vivo. Since inhibition of PDI prevents platelet accumulation and fibrin generation, it makes it a valuable target for the development of new antithrombotics. Rutin, a flavonol glycoside derivative of Quercetin, was previously described for displaying decent potency against PDI, and it inhibited the agonist-induced platelets aggregation in vivo, however its utility is limited by its low solubility and its off-target activity. Rutin was recently reported to bind specifically to the b' domain of PDI affecting protein flexibility which results in the inhibition of its reductase activity. To investigate Rutin inhibitory mechanism we used docking and molecular dynamics simulation and we observed that Rutin binds to a specific hydrophobic pocket of the b' domain which reduces PDI flexibility. Methods: In an attempt to identify more potent, soluble and specific PDI inhibitors, we established an in silico approach based on similarity search in Zinc Drug-like library composed of more than 17 million compounds satisfying Lipiniski's rule of five. A KNIME workflow was established for selecting Rutin-similar compounds based on Tanimoto coefficients. Then, a virtual screening of selected compounds was performed using Autodock Vina on PDI target pocket. In order to select PDI specific probes, a counter-screen was run to eliminate hits binding Erp57 thioredoxin active site. Hits were then submitted to druglikeness prediction using Quantitative Estimate of Druglikeness (QED). A total of 5 compounds were selected and submitted to re-docking with Autodock Vina. Complexes were subject to Molecular Dynamics simulation using NAMD. Results and Discussion: a total of 4 compounds were shown to form stable complexes with PDI binding pocket and then could constitute promising candidates for lead optimization. In conclusion, our in silico approach lead to the identification of potential novel PDI inhibitors that may form suitable candidates for Arterial thrombosis drug discovery.

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Copper‐Promoted Tandem Radical Reaction of 2‐Oxindoles with Formamides: Facile Synthesis of Unsymmetrical Urea Derivatives

et al. 2018

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Ac onvenient copper-promoted tandemr adical reaction of 2-oxindoles with formamidesp roducing unsymmetrical urea derivatives is described. This radicalmediated reaction enables the formation of one C=Oa nd one CÀNb ond through ad omino CÀOc oupling, ring cleavage and CÀNc oupling process,w hich features a broad substrate scope and excellent selectivity.I na ddition, tBuOOH not only acts as the oxidant, but also as the oxygen source.T he proposed reactionm echanism is supported by control experiments.

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Mining biologically-active molecules for inhibitors of fatty acid amide hydrolase (FAAH): Identification of phenmedipham and amperozide as FAAH inhibitors

Cited by 9 publications

References 41 publications

ω‐Phthalimidoalkyl Aryl Ureas as Potent and Selective Inhibitors of Cholesterol Esterase

ω‐Phthalimidoalkyl Aryl Ureas as Potent and Selective Inhibitors of Cholesterol Esterase

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Copper‐Promoted Tandem Radical Reaction of 2‐Oxindoles with Formamides: Facile Synthesis of Unsymmetrical Urea Derivatives

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