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1.
Biomed Pharmacother ; 153: 113359, 2022 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-35785702

RESUMEN

Inhibitors of dopamine transporters (DAT), norepinephrine transporters (NET) and serotonin transporters (SERT) are effective treatments for neuropsychiatric diseases. Dasotraline [(1R,4 S)- 4-(3,4-dichlorophenyl)- 1,2,3,4-tetrahydro-1-naphthalenamine, also known as SEP-225289) was evaluated for its inhibitory potency at DAT, NET and SERT using in vitro and in vivo assays. In vitro radiometric functional uptake studies showed preferential inhibition by dasotraline of hDAT (IC50 =3 nM) and hNET (IC50 =4 nM relative to hSERT(IC50 =15 nM). In mouse ex vivo occupancy studies, dasotraline demonstrated total plasma concentration-dependent occupancy at DAT, NET and SERT. Determination of the TO50 (50% transporter occupancy) were 32, 109 and 276 ng/ml, respectively. In SPECT imaging studies in baboons, dasotraline (0.2 mg/kg iv) displaced radiotracer binding to DAT by 87% but only 20% at NET and SERT. Rat microdialysis studies were performed in prefrontal cortex and striatum. Dasotraline produced sustained (>4 h) increases in dopamine and norepinephrine concentrations. Dasotraline was also more potent at increasing synaptic dopamine in the striatum, and norepinephrine in the prefrontal cortex than serotonin in these regions. In summary, dasotraline preferentially inhibits DAT and NET relative to SERT. Together, the occupancy and neurochemical profile of dasotraline provide a mechanistic basis for the treatment of diseases that have an underlying causality involving dopamine and norepinephrine dysfunction.


Asunto(s)
Dopamina , Proteínas de Transporte de Noradrenalina a través de la Membrana Plasmática , 1-Naftilamina/análogos & derivados , Animales , Dopamina/metabolismo , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/metabolismo , Ratones , Norepinefrina/metabolismo , Proteínas de Transporte de Noradrenalina a través de la Membrana Plasmática/metabolismo , Ratas , Serotonina/metabolismo , Proteínas de Transporte de Serotonina en la Membrana Plasmática/metabolismo
2.
Behav Brain Res ; 396: 112902, 2021 01 01.
Artículo en Inglés | MEDLINE | ID: mdl-32926906

RESUMEN

To interrogate whether altered function of the hippocampal-mPFC circuit underlies the deficit in fear extinction recall in rats subjected to single-prolonged stress (SPS), changes in brain region-specific metabolic rate were measured in male rats (control and SPS treated). Brain region metabolic rates were quantified using uptake of 14C-2-deoxyglucose (14C-2DG) during fear memory formation, fear memory extinction and extinction recall. Control and SPS rats had similar regional brain activities at baseline. During extinction recall, 14C-2DG uptake decreased in hippocampal regions in control rats, but not in SPS rats. SPS rats also exhibited a significant deficiency in fear extinction recall, replicating a previously reported finding. Reduced hippocampal activity during fear extinction recall in control animals may reflect reduction in fear overgeneralization, thereby enabling discrimination between distinct contexts. In contrast, persistent levels of hippocampal activity in SPS-exposed male animals during fear extinction recall may reflect the dysfunctional persistence of fear overgeneralization. Future studies in females can test gender-specificity of these effects, with appropriate attention to luteal dependent effects on extinction of fear learning. Detailed knowledge of regional brain activities underlying stress-induced deficits in extinction recall may help identify therapeutic targets in PTSD.


Asunto(s)
Extinción Psicológica/fisiología , Miedo/fisiología , Generalización Psicológica/fisiología , Hipocampo/fisiopatología , Recuerdo Mental/fisiología , Trastornos por Estrés Postraumático/fisiopatología , Animales , Autorradiografía , Radioisótopos de Carbono , Desoxiglucosa , Modelos Animales de Enfermedad , Hipocampo/metabolismo , Masculino , Ratas , Ratas Sprague-Dawley , Trastornos por Estrés Postraumático/metabolismo
3.
CNS Neurosci Ther ; 22(5): 404-12, 2016 May.
Artículo en Inglés | MEDLINE | ID: mdl-26849844

RESUMEN

INTRODUCTION: SEP-432 is a triple monoamine reuptake inhibitor of norepinephrine (NE), serotonin (5-HT), and dopamine (DA), based on in vitro binding studies. We sought evidence that SEP-432 engages these monoamine systems by measuring concentrations of monoamines and/or their main metabolites in cerebrospinal fluid (CSF) and plasma and comparing results to duloxetine, a dual reuptake inhibitor of NE and 5-HT. METHODS: Eighteen healthy normal subjects received either SEP-432 (300 mg/day), duloxetine (60 mg/day), or placebo for 14 days in-clinic (double blind) with CSF and plasma collections at baseline (single lumbar puncture) and Day 14 (24-h CSF and plasma collection). Concentrations of monoamines and their metabolites, as well as pharmacokinetic concentrations of SEP-432 and metabolite, were quantified by liquid chromatography-tandem mass spectrometry. RESULTS: Compared to placebo in the Day 14 area under the curve 24-h (AUC0-24 h ) analysis, SEP-432 significantly (P < 0.05) decreased the NE metabolite dihydroxyphenylglycol (DHPG) in CSF and plasma, decreased 5-HT in plasma, and did not affect DA metabolites, while duloxetine had significant effects on DHPG and 5-HT. Time-matched baseline to Day 14 biomarker comparisons confirmed these findings. CONCLUSION: CSF monoamine biomarkers confirmed central NET activity for SEP-432 and duloxetine's dual reuptake inhibition.


Asunto(s)
Biomarcadores Farmacológicos/sangre , Biomarcadores Farmacológicos/líquido cefalorraquídeo , Clorhidrato de Duloxetina/farmacología , Neurotransmisores/sangre , Neurotransmisores/líquido cefalorraquídeo , Inhibidores de la Captación de Neurotransmisores/farmacología , Adulto , Monoaminas Biogénicas/sangre , Monoaminas Biogénicas/líquido cefalorraquídeo , Cromatografía Líquida de Alta Presión , Ciclohexanoles/farmacología , Dimetilaminas/farmacología , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Electrocardiografía , Femenino , Voluntarios Sanos , Humanos , Masculino , Metoxihidroxifenilglicol/análogos & derivados , Metoxihidroxifenilglicol/metabolismo , Persona de Mediana Edad , Espectrometría de Masas en Tándem , Factores de Tiempo , Adulto Joven
4.
Biosci Rep ; 34(4)2014 Aug 11.
Artículo en Inglés | MEDLINE | ID: mdl-25001371

RESUMEN

The NMDAR (N-methyl-D-aspartate receptor) is a central regulator of synaptic plasticity and learning and memory. hDAAO (human D-amino acid oxidase) indirectly reduces NMDAR activity by degrading the NMDAR co-agonist D-serine. Since NMDAR hypofunction is thought to be a foundational defect in schizophrenia, hDAAO inhibitors have potential as treatments for schizophrenia and other nervous system disorders. Here, we sought to identify novel chemicals that inhibit hDAAO activity. We used computational tools to design a focused, purchasable library of compounds. After screening this library for hDAAO inhibition, we identified the structurally novel compound, 'compound 2' [3-(7-hydroxy-2-oxo-4-phenyl-2H-chromen-6-yl)propanoic acid], which displayed low nM hDAAO inhibitory potency (Ki=7 nM). Although the library was expected to enrich for compounds that were competitive for both D-serine and FAD, compound 2 actually was FAD uncompetitive, much like canonical hDAAO inhibitors such as benzoic acid. Compound 2 and an analog were independently co-crystalized with hDAAO. These compounds stabilized a novel conformation of hDAAO in which the active-site lid was in an open position. These results confirm previous hypotheses regarding active-site lid flexibility of mammalian D-amino acid oxidases and could assist in the design of the next generation of hDAAO inhibitors.


Asunto(s)
Dominio Catalítico/efectos de los fármacos , D-Aminoácido Oxidasa/antagonistas & inhibidores , Inhibidores Enzimáticos/farmacología , Proteínas Portadoras/metabolismo , Humanos , Receptores de N-Metil-D-Aspartato/metabolismo , Esquizofrenia/metabolismo , Serina/metabolismo
5.
J Med Chem ; 56(9): 3710-24, 2013 May 09.
Artículo en Inglés | MEDLINE | ID: mdl-23631755

RESUMEN

We characterized the mechanism and pharmacodynamics of five structurally distinct inhibitors of d-amino acid oxidase. All inhibitors bound the oxidized form of human enzyme with affinity slightly higher than that of benzoate (Kd ≈ 2-4 µM). Stopped-flow experiments showed that pyrrole-based inhibitors possessed high affinity (Kd ≈ 100-200 nM) and slow release kinetics (k < 0.01 s(-1)) in the presence of substrate, while inhibitors with pendent aromatic groups altered conformations of the active site lid, as evidenced by X-ray crystallography, and showed slower kinetics of association. Rigid bioisosteres of benzoic acid induced a closed-lid conformation, had slower release in the presence of substrate, and were more potent than benzoate. Steady-state d-serine concentrations were described in a PK/PD model, and competition for d-serine sites on NMDA receptors was demonstrated in vivo. DAAO inhibition increased the spatiotemporal influence of glial-derived d-serine, suggesting localized effects on neuronal circuits where DAAO can exert a neuromodulatory role.


Asunto(s)
D-Aminoácido Oxidasa/antagonistas & inhibidores , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Bibliotecas de Moléculas Pequeñas/química , Bibliotecas de Moléculas Pequeñas/farmacología , Animales , Conducta Animal/efectos de los fármacos , Unión Competitiva , Dominio Catalítico , D-Aminoácido Oxidasa/química , D-Aminoácido Oxidasa/metabolismo , Inhibidores Enzimáticos/metabolismo , Inhibidores Enzimáticos/farmacocinética , Glicina/metabolismo , Humanos , Cinética , Masculino , Simulación del Acoplamiento Molecular , Neuroglía/efectos de los fármacos , Neuroglía/metabolismo , Ratas , Ratas Sprague-Dawley , Serina/biosíntesis , Bibliotecas de Moléculas Pequeñas/metabolismo , Bibliotecas de Moléculas Pequeñas/farmacocinética
6.
J Med Chem ; 54(15): 5283-95, 2011 Aug 11.
Artículo en Inglés | MEDLINE | ID: mdl-21739935

RESUMEN

The present work expands the chemical space known to offer potent inhibition of the serotonin transporter (SERT), norepinephrine transporter (NET), and dopamine transporter (DAT) and discloses novel bicyclic octahydrocyclopenta[c]pyrrole and octahydro-1H-isoindole scaffolds as potent triple reuptake inhibitors (TRIs) for the potential treatment of depression. Optimized compounds 22a (SERT, NET, DAT, IC(50) = 20, 109, 430 nM), 23a (SERT, NET, DAT, IC(50) = 29, 85, 168 nM), and 26a (SERT, NET, DAT, IC(50) = 53, 150, 140 nM) were highly brain penetrant, active in vivo in the mouse tail suspension test at 10 and 30 mpk PO, and were not generally motor stimulants at doses ranging from 1 to 30 mpk PO. Moderate in vitro cytochrome P450 (CYP) and potassium ion channel Kv11.1 (hERG) inhibition were uncovered as potential liabilities for the chemical series.


Asunto(s)
Pirroles/síntesis química , Inhibidores Selectivos de la Recaptación de Serotonina/síntesis química , Animales , Antidepresivos/síntesis química , Antidepresivos/farmacología , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/antagonistas & inhibidores , Concentración 50 Inhibidora , Isoindoles/síntesis química , Isoindoles/farmacología , Ratones , Actividad Motora/efectos de los fármacos , Proteínas de Transporte de Noradrenalina a través de la Membrana Plasmática/antagonistas & inhibidores , Pirroles/farmacología , Ratas , Proteínas de Transporte de Serotonina en la Membrana Plasmática/efectos de los fármacos , Inhibidores Selectivos de la Recaptación de Serotonina/farmacología , Relación Estructura-Actividad
7.
Bioorg Med Chem Lett ; 21(5): 1438-41, 2011 Mar 01.
Artículo en Inglés | MEDLINE | ID: mdl-21310609

RESUMEN

The current work discloses a novel cyclohexylarylamine chemotype with potent inhibition of the serotonin, norepinephrine, and dopamine transporters and potential for treatment of major depressive disorder. Optimized compounds 1 (SERT, NET, DAT, IC(50)=169, 85, 21 nM) and 42 (SERT, NET, DAT IC(50)=34, 295, 90 nM) were highly brain penetrant, active in vivo in the mouse tail suspension test at 30 mpk po and were not general motor stimulants.


Asunto(s)
Aminas/síntesis química , Inhibidores de Captación de Dopamina , Diseño de Fármacos , Metano/síntesis química , Norepinefrina , Serotonina , Aminas/química , Aminas/farmacología , Animales , Antidepresivos/síntesis química , Antidepresivos/química , Antidepresivos/farmacología , Ciclización , Inhibidores de Captación de Dopamina/síntesis química , Inhibidores de Captación de Dopamina/química , Inhibidores de Captación de Dopamina/farmacología , Concentración 50 Inhibidora , Metano/química , Metano/farmacología , Ratones , Estructura Molecular , Norepinefrina/síntesis química , Norepinefrina/química , Norepinefrina/farmacología , Ratas , Serotonina/síntesis química , Serotonina/química , Serotonina/farmacología , Estereoisomerismo
8.
Bioorg Med Chem Lett ; 21(5): 1434-7, 2011 Mar 01.
Artículo en Inglés | MEDLINE | ID: mdl-21310612

RESUMEN

Novel chiral cyclohexylaryl amines were developed with potent reuptake inhibition against the serotonin, norepinephrine and dopamine transporters and activity at 10 and 30 mpk PO in the mouse tail suspension test. Prototype compound 31 (SERT, NET, DAT IC(50) ≤ 1, 21, 28 nM) was highly brain penetrant, had minimal CYP and hERG inhibition, and represents a previously undisclosed architecture with potential for treatment of major depressive disorder.


Asunto(s)
Aminas/síntesis química , Inhibidores de Captación de Dopamina , Diseño de Fármacos , Norepinefrina , Serotonina , Aminas/química , Aminas/farmacología , Animales , Ciclización , Inhibidores de Captación de Dopamina/síntesis química , Inhibidores de Captación de Dopamina/química , Inhibidores de Captación de Dopamina/farmacología , Concentración 50 Inhibidora , Ratones , Estructura Molecular , Norepinefrina/síntesis química , Norepinefrina/química , Norepinefrina/farmacología , Serotonina/síntesis química , Serotonina/química , Serotonina/farmacología , Estereoisomerismo
9.
Bioorg Med Chem Lett ; 21(1): 520-3, 2011 Jan 01.
Artículo en Inglés | MEDLINE | ID: mdl-21095126

RESUMEN

The present work describes a series of novel tetrahydroquinoline amines that potently inhibit the in vitro reuptake of serotonin and dopamine (dual reuptake inhibitors). The compounds are structurally related to a series we disclosed previously, but are improved with respect to cytochrome P-450 enzyme (CYP) and potassium ion channel Kv11.1 (hERG) inhibition and synthetic accessibility. The detailed synthesis and in vitro activity and ADME profile of the compounds is described, which represent a previously undisclosed dual reuptake inhibitor chemotype.


Asunto(s)
Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/antagonistas & inhibidores , Inhibidores de Captación de Dopamina/química , Quinolinas/química , Inhibidores Selectivos de la Recaptación de Serotonina/química , Proteínas de Transporte de Serotonina en la Membrana Plasmática/química , Animales , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/metabolismo , Inhibidores de Captación de Dopamina/síntesis química , Inhibidores de Captación de Dopamina/farmacocinética , Evaluación Preclínica de Medicamentos , Humanos , Ratones , Microsomas/metabolismo , Quinolinas/síntesis química , Quinolinas/farmacocinética , Proteínas de Transporte de Serotonina en la Membrana Plasmática/metabolismo , Inhibidores Selectivos de la Recaptación de Serotonina/síntesis química , Inhibidores Selectivos de la Recaptación de Serotonina/farmacocinética
10.
Bioorg Med Chem ; 19(1): 663-76, 2011 Jan 01.
Artículo en Inglés | MEDLINE | ID: mdl-21093273

RESUMEN

The present work describes a series of novel chiral amines that potently inhibit the in vitro reuptake of serotonin, norepinephrine and dopamine (triple reuptake inhibitors) and were active in vivo in a mouse model predictive of antidepressant like activity. The detailed synthesis and in vitro activity and ADME profile of compounds is described, which represent a previously undisclosed triple reuptake inhibitor chemotype.


Asunto(s)
Naftalenos/síntesis química , Naftalenos/farmacología , Inhibidores de la Captación de Neurotransmisores/síntesis química , Inhibidores de la Captación de Neurotransmisores/farmacología , Animales , Antidepresivos/síntesis química , Antidepresivos/farmacología , Modelos Animales de Enfermedad , Dopamina/metabolismo , Evaluación Preclínica de Medicamentos , Ratones , Norepinefrina/metabolismo , Serotonina/metabolismo
11.
J Mol Biol ; 352(1): 105-16, 2005 Sep 09.
Artículo en Inglés | MEDLINE | ID: mdl-16055151

RESUMEN

Pteridine reductase (PTR1) is an NADPH-dependent short-chain reductase found in parasitic trypanosomatid protozoans. The enzyme participates in the salvage of pterins and represents a target for the development of improved therapies for infections caused by these parasites. A series of crystallographic analyses of Leishmania major PTR1 are reported. Structures of the enzyme in a binary complex with the cofactor NADPH, and ternary complexes with cofactor and biopterin, 5,6-dihydrobiopterin, and 5,6,7,8-tetrahydrobiopterin reveal that PTR1 does not undergo any major conformational changes to accomplish binding and processing of substrates, and confirm that these molecules bind in a single orientation at the catalytic center suitable for two distinct reductions. Ternary complexes with cofactor and CB3717 and trimethoprim (TOP), potent inhibitors of thymidylate synthase and dihydrofolate reductase, respectively, have been characterized. The structure with CB3717 reveals that the quinazoline moiety binds in similar fashion to the pterin substrates/products and dominates interactions with the enzyme. In the complex with TOP, steric restrictions enforced on the trimethoxyphenyl substituent prevent the 2,4-diaminopyrimidine moiety from adopting the pterin mode of binding observed in dihydrofolate reductase, and explain the inhibition properties of a range of pyrimidine derivates. The molecular detail provided by these complex structures identifies the important interactions necessary to assist the structure-based development of novel enzyme inhibitors of potential therapeutic value.


Asunto(s)
Leishmania major/enzimología , Oxidorreductasas/química , Estructura Cuaternaria de Proteína , Animales , Sitios de Unión , Biopterinas/química , Biopterinas/metabolismo , Cristalografía por Rayos X , Antagonistas del Ácido Fólico/metabolismo , Humanos , Enlace de Hidrógeno , Ligandos , Sustancias Macromoleculares , Modelos Moleculares , Datos de Secuencia Molecular , Estructura Molecular , Oxidorreductasas/antagonistas & inhibidores , Oxidorreductasas/genética , Oxidorreductasas/metabolismo , Unión Proteica , Trimetoprim/metabolismo
12.
Biotechnol Prog ; 21(1): 300-8, 2005.
Artículo en Inglés | MEDLINE | ID: mdl-15903269

RESUMEN

A facile and cost-effective process for screening synthetic libraries for an affinity ligand is described. A high throughput 96-well plate filtration method was designed to screen both discrete compounds and mixtures of compounds attached to a solid support. Human serum albumin (HSA) was used as a target protein to demonstrate the proof of concept. Detection and quantitation by fluorescence was accomplished with the use of fluorescamine to conjugate the protein in the filtrate. It is found that mixtures demonstrating low average binding reflect an overall lower hit rate of the components, whereas deconvolution of mixtures with high protein binding consistently provides a high hit rate. This differs from many of the previous experiences screening solid-phase mixtures in which high false positive rates are noted to occur. A total of 100K compounds were tested: 25K as discrete samples and 75K as mixtures. An overall hit rate of 8% was observed. Secondary screening of compounds measured specificity, recovery, and dynamic binding capacity. The effectiveness of the method is illustrated using an affinity column made with a representative lead compound. A similar purity was achieved in a single-step purification of HSA from serum as compared to that obtained by two steps of ion-exchange chromatography. The process for primary screening of a large number of compounds is simple, inexpensive, and applicable to any soluble target protein of known or unknown function from crude mixtures and may have additional utility as a generic chemical affinity tool for the functional characterization of novel proteins emerging from proteomics work.


Asunto(s)
Cromatografía de Afinidad , Técnicas Químicas Combinatorias/métodos , Albúmina Sérica/química , Técnicas Químicas Combinatorias/economía , Humanos , Ligandos , Unión Proteica/fisiología , Sensibilidad y Especificidad
13.
Bioorg Med Chem ; 13(6): 2141-56, 2005 Mar 15.
Artículo en Inglés | MEDLINE | ID: mdl-15727867

RESUMEN

Trypanosoma cruzi, a protozoan parasite, is the causative agent of Chagas disease, a major cause of cardiovascular disease in many Latin American countries. There is an urgent need to develop an improved therapy due to the toxicity of existing drugs and emerging drug resistance. Cruzain, the primary cysteine protease of T. cruzi, is essential for the survival of the parasite in host cells and therefore is an important target for the development of inhibitors as potential therapeutics. A novel series of alpha-ketoamide-, alpha-ketoacid-, alpha-ketoester-, and aldehyde-based inhibitors of cruzain has been developed. The inhibitors were identified by screening protease targeted small molecule libraries and systematically optimizing the P1, P2, P3, and P1' residues using specific structure-guided methods. A total of 20 compounds displayed picomolar potency in in vitro assays and three inhibitors representing different alpha-keto-based inhibitor scaffolds demonstrated anti-trypanosomal activity in cell culture. A 2.3A crystallographic structure of cruzain bound with one of the alpha-ketoester analogs is also reported. The structure and kinetic assay data illustrate the covalent binding, reversible inhibition mechanism of the inhibitor. Information on the compounds reported here will be useful in the development of new lead compounds as potential therapeutic agents for the treatment of Chagas disease and as biological probes to study the role that cruzain plays in the pathology. This study also demonstrates the validity of structure-guided approaches to focused library design and lead compound optimization.


Asunto(s)
Enfermedad de Chagas/tratamiento farmacológico , Enfermedad de Chagas/parasitología , Inhibidores de Cisteína Proteinasa/química , Inhibidores de Cisteína Proteinasa/farmacología , Diseño de Fármacos , Proteínas Protozoarias/antagonistas & inhibidores , Trypanosoma cruzi/enzimología , Amidas/química , Animales , Línea Celular , Cristalografía por Rayos X , Cisteína Endopeptidasas/química , Cisteína Endopeptidasas/metabolismo , Inhibidores de Cisteína Proteinasa/síntesis química , Inhibidores de Cisteína Proteinasa/uso terapéutico , Ésteres/química , Concentración 50 Inhibidora , Cinética , Ratones , Modelos Moleculares , Estructura Molecular , Proteínas Protozoarias/química , Proteínas Protozoarias/metabolismo
14.
Drug Discov Today ; 9(3): 117-26, 2004 Feb 01.
Artículo en Inglés | MEDLINE | ID: mdl-14960389

RESUMEN

Many genetic (gene deletion, interruption or mutation), epigenetic (such as antisense or small interfering RNA) and immunological methods are being applied in 'high-throughput target validation' studies of the novel potential targets arising from whole genome sequencing. Such applications often focus on 'loss of function' approaches. However, target validation is most reliable when multiple orthogonal approaches are used. Initiating a target-based discovery project based on correlative evidence is faster than awaiting causative evidence. Indeed, the multiple tools needed to generate firm proof usually include methods and reagents only generated after starting a discovery project with little evidence beyond correlations. Robust and rigorous tests of whether a drug candidate is efficacious in vivo because of its effects on a specific molecular particular target are best made by simultaneously applying multiple orthogonal tools. Examples of the orthogonal tools approach will be discussed.


Asunto(s)
Sistemas de Liberación de Medicamentos , Diseño de Fármacos , Tecnología Farmacéutica/métodos , Animales , Animales Modificados Genéticamente , Línea Celular , Evaluación Preclínica de Medicamentos , Humanos
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