RESUMEN
The current standard of care for hepatitis C virus (HCV)-infected patients consists of lengthy treatment with interferon and ribavirin. To increase the effectiveness of HCV therapy, future regimens will incorporate multiple direct-acting antiviral (DAA) drugs. Recently, the HCV-encoded NS5A protein has emerged as a promising DAA target. Compounds targeting NS5A exhibit remarkable potency in vitro and demonstrate early clinical promise, suggesting that NS5A inhibitors could feature in future DAA combination therapies. Since the mechanisms through which these molecules operate are unknown, we have used NS5A inhibitors as tools to investigate their modes of action. Analysis of replicon-containing cells revealed dramatic phenotypic alterations in NS5A localization following treatment with NS5A inhibitors; NS5A was redistributed from the endoplasmic reticulum to lipid droplets. The NS5A relocalization did not occur in cells treated with other classes of HCV inhibitors, and NS5A-targeting molecules did not cause similar alterations in the localization of other HCV-encoded proteins. Time course analysis of the redistribution of NS5A revealed that the transfer of protein to lipid droplets was concomitant with the onset of inhibition, as judged by the kinetic profiles for these compounds. Furthermore, analysis of the kinetic profile of inhibition for a panel of test molecules permitted the separation of compounds into different kinetic classes based on their modes of action. Results from this approach suggested that NS5A inhibitors perturbed the function of new replication complexes, rather than acting on preformed complexes. Taken together, our data reveal novel biological consequences of NS5A inhibition, which may help enable the development of future assay platforms for the identification of new and/or different NS5A inhibitors.
Asunto(s)
Antivirales/farmacología , Retículo Endoplásmico/metabolismo , Imidazoles/farmacología , Proteínas no Estructurales Virales/antagonistas & inhibidores , Antivirales/química , Carbamatos , Línea Celular Tumoral , Retículo Endoplásmico/ultraestructura , Hepacivirus/efectos de los fármacos , Hepacivirus/genética , Hepatocitos/ultraestructura , Hepatocitos/virología , Humanos , Imidazoles/química , Concentración 50 Inhibidora , Lípidos , Microscopía Confocal , Modelos Moleculares , Pirrolidinas , Replicón , Bibliotecas de Moléculas Pequeñas , Valina/análogos & derivados , Proteínas no Estructurales Virales/metabolismo , Replicación ViralRESUMEN
N-(o-Halophenyl)imidoyl chlorides and the corresponding imidates are easily prepared and can be utilized as complementary precursors for the synthesis of important heterocycles. The synthesis of N-substituted benzimidazoles was possible from the palladium-catalyzed reaction of both classes of substrate with a variety of N-nucleophiles. The use of the imidate precursor for the synthesis of N-substituted quinazolinones by incorporation of a palladium-catalyzed aminocarbonylation reaction has also been demonstrated. Both processes tolerate a wide range of functional groups.
Asunto(s)
Bencimidazoles/síntesis química , Paladio/química , Quinazolinonas/síntesis química , Bencimidazoles/química , Catálisis , Estructura Molecular , Quinazolinonas/química , EstereoisomerismoRESUMEN
New N-(1,2-diphenylethyl)piperazines 6 are disclosed as dual serotonin and noradrenaline reuptake inhibitors (SNRI) which may have potential in treating stress urinary incontinence (SUI). In this Letter, we present new data for SNRI PF-526014 (4) including performance in a canine in vivo model of SUI, cardiovascular assessment, pharmacokinetics in dog and determination of the primary routes of metabolism in vitro. Starting from 4, detailed structure activity relationships established that potent dual SNRIs could be achieved by appropriate substitution of the phenyl rings (6: R; R(1)) combined with a preferred stereochemistry. From this set of compounds, piperazine (-)-6a was identified as a potent and selective dual SNRI with improved metabolic stability and reduced ion channel activity when compared to 4. Based on this profile, (-)-6a was selected for further evaluation in a preclinical model of SUI.
Asunto(s)
Inhibidores de Captación Adrenérgica/química , Norepinefrina , Piperazinas/química , Inhibidores Selectivos de la Recaptación de Serotonina/química , Incontinencia Urinaria de Esfuerzo/tratamiento farmacológico , Inhibidores de Captación Adrenérgica/metabolismo , Inhibidores de Captación Adrenérgica/farmacocinética , Animales , Perros , Humanos , Piperazinas/metabolismo , Piperazinas/farmacología , Inhibidores Selectivos de la Recaptación de Serotonina/metabolismo , Inhibidores Selectivos de la Recaptación de Serotonina/farmacocinética , Relación Estructura-ActividadRESUMEN
Derivatives of N-[(3S)-pyrrolidin-3-yl]benzamides are disclosed as a new series of noradrenaline reuptake inhibitors (NRI). Structure-activity relationships established that potent NRI activity could be achieved by appropriate substitution at the 2-position of the phenyl ring; consequently, selective NRIs and dual NSRIs were prepared. Benzamide 11e was identified as a potent NRI with good selectivity over SRI and DRI, good in vitro metabolic stability, weak CYP inhibition and low affinity for ion channels. Evaluation in vivo, in rat microdialysis experiments, showed 11e increased noradrenaline levels by up to 350% confirming good CNS penetration. Benzamide 11e was differentiated from previous NRIs as it was significantly less lipophilic (DeltaclogP -0.9).
Asunto(s)
Inhibidores de Captación Adrenérgica/síntesis química , Benzamidas/síntesis química , Fármacos del Sistema Nervioso Central/síntesis química , Sistema Nervioso Central/metabolismo , Norepinefrina/metabolismo , Pirrolidinas/síntesis química , Inhibidores de Captación Adrenérgica/química , Inhibidores de Captación Adrenérgica/farmacología , Animales , Benzamidas/química , Benzamidas/farmacología , Línea Celular , Fármacos del Sistema Nervioso Central/química , Fármacos del Sistema Nervioso Central/farmacología , Diseño de Fármacos , Humanos , Microsomas Hepáticos/metabolismo , Pirrolidinas/química , Pirrolidinas/farmacología , RatasRESUMEN
Single enantiomer [(aryloxy)(pyridinyl)methyl]piperidine and pyrrolidine derivatives 5-9 are inhibitors of monoamine reuptake. Structure-activity relationships established that monoamine reuptake inhibition are functions of amine, pyridine isomer, aryloxy ring substitution and stereochemistry. Consequently, selective NRIs, selective SRIs, dual SNRIs and triple SNDRIs were all identified. Dual SNRIs 5l-a and 9c were evaluated in additional pharmacology and pharmacokinetic studies as representative examples from this series.
Asunto(s)
Inhibidores de Captación Adrenérgica/química , Norepinefrina/metabolismo , Piperidinas/química , Pirrolidinas/química , Inhibidores Selectivos de la Recaptación de Serotonina/química , Inhibidores de Captación Adrenérgica/síntesis química , Inhibidores de Captación Adrenérgica/farmacocinética , Animales , Diseño de Fármacos , Piperidinas/síntesis química , Piperidinas/farmacocinética , Pirrolidinas/síntesis química , Pirrolidinas/farmacocinética , Ratas , Serotonina/metabolismo , Inhibidores Selectivos de la Recaptación de Serotonina/síntesis química , Inhibidores Selectivos de la Recaptación de Serotonina/farmacocinética , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
The structure-activity relationship and the synthesis of novel N-[(3S)-pyrrolidin-3-yl]benzamides as dual serotonin and noradrenaline monoamine reuptake inhibitors (SNRI) is described. Preferred compound 9 aka PF-184,298 is a potent SNRI with good selectivity over dopamine reuptake inhibition (DRI), good in vitro metabolic stability, weak CYP inhibition and drug-like physicochemical properties consistent with CNS target space. Evaluation in an in vivo preclinical model of stress urinary incontinence showed 9 significantly increased urethral tone at free plasma concentrations consistent with its in vitro primary pharmacology.
Asunto(s)
Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/metabolismo , Inhibidores de Captación Adrenérgica/química , Anilidas/química , Benzamidas/química , Sistema Nervioso Central/metabolismo , Pirrolidinas/química , Inhibidores Selectivos de la Recaptación de Serotonina/química , Inhibidores de Captación Adrenérgica/síntesis química , Inhibidores de Captación Adrenérgica/farmacocinética , Anilidas/síntesis química , Anilidas/farmacología , Animales , Benzamidas/síntesis química , Benzamidas/farmacocinética , Línea Celular , Perros , Inhibidores de Captación de Dopamina/síntesis química , Inhibidores de Captación de Dopamina/química , Inhibidores de Captación de Dopamina/farmacocinética , Humanos , Norepinefrina/metabolismo , Pirrolidinas/síntesis química , Pirrolidinas/farmacología , Ratas , Inhibidores Selectivos de la Recaptación de Serotonina/síntesis química , Inhibidores Selectivos de la Recaptación de Serotonina/farmacocinética , Relación Estructura-ActividadRESUMEN
[4-(Phenoxy)pyridine-3-yl]methylamines are disclosed as a new series of selective noradrenaline reuptake inhibitors (NRI). Structure-activity relationships established that potent NRI activity could be achieved by appropriate substitution at the 2-position of the phenoxy ring. Compound 31 demonstrated potent NRI activity combined with good selectivity over serotonin and dopamine reuptake and no significant off-target pharmacology.
Asunto(s)
Inhibidores de Captación Adrenérgica/farmacología , Metilaminas/farmacología , Norepinefrina/antagonistas & inhibidores , Piridinas/farmacología , Inhibidores de Captación Adrenérgica/síntesis química , Animales , Transporte Biológico , Células CACO-2 , Inhibidores Enzimáticos del Citocromo P-450 , Dopamina/metabolismo , Inhibidores de Captación de Dopamina/farmacología , Canales de Potasio Éter-A-Go-Go/metabolismo , Líquido Extracelular/efectos de los fármacos , Hepatocitos/efectos de los fármacos , Hepatocitos/metabolismo , Humanos , Metilaminas/síntesis química , Microdiálisis , Microsomas Hepáticos/efectos de los fármacos , Microsomas Hepáticos/metabolismo , Estructura Molecular , Corteza Prefrontal/efectos de los fármacos , Piridinas/síntesis química , Ratas , Serotonina/metabolismo , Inhibidores Selectivos de la Recaptación de Serotonina/farmacología , Relación Estructura-ActividadRESUMEN
A novel series of pyridyl-phenyl ethers are disclosed, which possess dual 5-HT and NA reuptake pharmacology with good selectivity over dopamine reuptake inhibition. An analysis of the relationship between lipophilicity and pharmacology highlighted that potent dual SNRI activity was only achievable at c log P>3.5. The series was found to possess significant polypharmacology issues, and we concluded that this off-target promiscuity was related to lipophilicity.
Asunto(s)
Aminas/farmacología , Hepatocitos/efectos de los fármacos , Norepinefrina/antagonistas & inhibidores , Éteres Fenílicos/farmacología , Piridinas/farmacología , Inhibidores Selectivos de la Recaptación de Serotonina/farmacología , Antagonistas del Receptor de Serotonina 5-HT1 , Aminas/síntesis química , Hepatocitos/metabolismo , Humanos , Concentración 50 Inhibidora , Modelos Químicos , Éteres Fenílicos/síntesis química , Piridinas/síntesis química , Inhibidores Selectivos de la Recaptación de Serotonina/síntesis química , Relación Estructura-ActividadRESUMEN
The structure-activity relationship and the synthesis of novel N-benzyl-N-(pyrrolidin-3-yl)carboxamides as dual serotonin (5-HT) and noradrenaline (NA) monoamine reuptake inhibitors are described. Compounds such as 18 exhibited dual 5-HT and NA reuptake inhibition, good selectivity over dopamine (DA) reuptake inhibition and drug-like physicochemical properties consistent with CNS target space. Compound 18 was selected for further preclinical evaluation.
Asunto(s)
Amidas/síntesis química , Amidas/farmacología , Norepinefrina/análisis , Pirrolidinas/síntesis química , Inhibidores Selectivos de la Recaptación de Serotonina/síntesis química , Serotonina/análisis , Amidas/química , Animales , Sistema Nervioso Central/efectos de los fármacos , Técnicas Químicas Combinatorias , Inhibidores del Citocromo P-450 CYP2D6 , Perros , Inhibidores de Captación de Dopamina/farmacología , Diseño de Fármacos , Hepatocitos/efectos de los fármacos , Hepatocitos/metabolismo , Humanos , Concentración 50 Inhibidora , Microsomas Hepáticos/efectos de los fármacos , Microsomas Hepáticos/metabolismo , Conformación Molecular , Pirrolidinas/farmacología , Inhibidores Selectivos de la Recaptación de Serotonina/química , Inhibidores Selectivos de la Recaptación de Serotonina/farmacología , Relación Estructura-ActividadRESUMEN
Derivatives of (3S)-N-(biphenyl-2-ylmethyl)pyrrolidin-3-amine are disclosed as a new series of noradrenaline reuptake inhibitors (NRI). Carboxamide 9e, carbamate 11b and sulfonamide 13a were identified as potent NRIs with excellent selectivity over SRI and DRI, good in vitro metabolic stability and weak CYP inhibition. Carbamate 11b demonstrated superior transit performance in MDCK-mdr1 cell lines with minimal P-gp efflux which was attributed to reduced HBA capacity of the carbamate group. Evaluation in vivo, in rat microdialysis experiments, showed 11b increased noradrenaline levels by 400% confirming good CNS penetration.
Asunto(s)
Pirrolidinas/síntesis química , Pirrolidinas/farmacología , Inhibidores Selectivos de la Recaptación de Serotonina/síntesis química , Inhibidores Selectivos de la Recaptación de Serotonina/farmacología , Animales , Sistema Nervioso Central/efectos de los fármacos , Técnicas Químicas Combinatorias , Humanos , Microsomas Hepáticos/efectos de los fármacos , Microsomas Hepáticos/metabolismo , Estructura Molecular , Pirrolidinas/química , Ratas , Inhibidores Selectivos de la Recaptación de Serotonina/química , EstereoisomerismoRESUMEN
Single enantiomer (SS) and (RR) 2-[(phenoxy)(phenyl)methyl]morpholine derivatives 5, 8-23 are inhibitors of monoamine reuptake. Target compounds were prepared using an enantioselective synthesis employing a highly specific enzyme-catalysed resolution of racemic n-butyl 4-benzylmorpholine-2-carboxylate (26) as the key step. Structure-activity relationships established that serotonin and noradrenaline reuptake inhibition are functions of stereochemistry and aryl/aryloxy ring substitution. Consequently, selective SRI, selective NRI and dual SNRIs were all identified. One of these compounds, a potent and selective dual SNRI, (SS)-5a was selected as a candidate for further pre-clinical evaluation.
Asunto(s)
Diseño de Fármacos , Morfolinas/síntesis química , Morfolinas/farmacología , Norepinefrina/metabolismo , Serotonina/metabolismo , Células Cultivadas , Humanos , Hígado/efectos de los fármacos , Hígado/metabolismo , Estructura Molecular , Morfolinas/química , Inhibidores Selectivos de la Recaptación de Serotonina/síntesis química , Inhibidores Selectivos de la Recaptación de Serotonina/química , Inhibidores Selectivos de la Recaptación de Serotonina/farmacología , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
By use of a structure-based computational method for identification of structurally novel Janus kinase (JAK) inhibitors predicted to bind beyond the ATP binding site, a potent series of indazoles was identified as selective pan-JAK inhibitors with a type 1.5 binding mode. Optimization of the series for potency and increased duration of action commensurate with inhaled or topical delivery resulted in potent pan-JAK inhibitor 2 (PF-06263276), which was advanced into clinical studies.
Asunto(s)
Antiinflamatorios/farmacología , Compuestos Heterocíclicos con 2 Anillos/farmacología , Indazoles/farmacología , Quinasas Janus/antagonistas & inhibidores , Enfermedades Pulmonares/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/farmacología , Enfermedades de la Piel/tratamiento farmacológico , Administración Cutánea , Administración por Inhalación , Animales , Antiinflamatorios/administración & dosificación , Antiinflamatorios/síntesis química , Antiinflamatorios/toxicidad , Sitios de Unión , Cristalografía por Rayos X , Perros , Diseño de Fármacos , Hepatocitos/metabolismo , Compuestos Heterocíclicos con 2 Anillos/administración & dosificación , Compuestos Heterocíclicos con 2 Anillos/síntesis química , Compuestos Heterocíclicos con 2 Anillos/toxicidad , Humanos , Indazoles/administración & dosificación , Indazoles/síntesis química , Indazoles/toxicidad , Janus Quinasa 1/antagonistas & inhibidores , Janus Quinasa 2/antagonistas & inhibidores , Janus Quinasa 3/antagonistas & inhibidores , Ratones Endogámicos BALB C , Microsomas Hepáticos/metabolismo , Fosforilación , Inhibidores de Proteínas Quinasas/administración & dosificación , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/toxicidad , Ratas , SolubilidadRESUMEN
During therapeutic interventions, blood concentrations of intravenously applied drugs are higher, and their onset of pharmacological action is faster than with other routes of drug administration. However, acute drug therapy often produces nephrotoxic side effects, as commonly seen after treatment with Ketorolac or Gentamicin leading to questions about their use, especially for patients at risk for acute renal failure. Omega-6(n-6) and omega-3(n-3) polyunsaturated fatty acids (PUFA) affect eicosanoid metabolism, which plays a role in the regulation of inflammation. Eicosanoids derived from n-6 FA have proinflammatory and immunoactive functions, whereas eicosanoids derived from n-3 PUFA have anti-inflammatory and cytoprotective properties. We hypothesized that providing such injectable drugs with nephrotoxic potential in combination with n3-PUFAs from the outset, might afford rapid cytoprotection of renal cells, given the recent evidence that intravenously administered n3-PUFAs are rapidly incorporated into cell membranes. We used intraglomerular mesangial cells (MES13) that are sensitive to treatment with Ketorolac or Gentamicin instead of proximal tubular cells which do not respond to Ketorolac. We found a significant inhibition of Ketorolac (0.25, 0.5, 1 mM) or Gentamicin (2.5, 5 mM) induced cytotoxicity after pretreatment of MES13 cells with 0.01% of 20%w/v LipOmega-3 Emulsion 9/1, containing 90:10 wt/wt mixture of fish oil derived triglycerides to medium chain triglycerides.
RESUMEN
Nonstructural protein 5A (NS5A) represents a novel target for the treatment of hepatitis C virus (HCV). Daclatasvir, recently reported by Bristol-Myers-Squibb, is a potent NS5A inhibitor currently under investigation in phaseâ 3 clinical trials. While the performance of daclatasvir has been impressive, the emergence of resistance could prove problematic and as such, improved analogues are being sought. By varying the biphenyl-imidazole unit of daclatasvir, novel inhibitors of HCV NS5A were identified with an improved resistance profile against mutant strains of the virus while retaining the picomolar potency of daclatasvir. One compound in particular, methyl ((S)-1-((S)-2-(4-(4-(6-(2-((S)-1-((methoxycarbonyl)-L-valyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)quinoxalin-2-yl)phenyl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-yl)carbamate (17), exhibited very promising activity and showed good absorption and a long predicted human pharmacokinetic half-life. This compound represents a promising lead that warrants further evaluation.
Asunto(s)
Inhibidores de Proteasas/química , Quinoxalinas/química , Valina/análogos & derivados , Proteínas no Estructurales Virales/antagonistas & inhibidores , Animales , Antivirales/síntesis química , Antivirales/química , Antivirales/farmacocinética , Línea Celular , Perros , Evaluación Preclínica de Medicamentos , Farmacorresistencia Viral , Semivida , Hepacivirus/metabolismo , Humanos , Microsomas Hepáticos/metabolismo , Inhibidores de Proteasas/farmacocinética , Quinoxalinas/síntesis química , Quinoxalinas/farmacocinética , Ratas , Relación Estructura-Actividad , Valina/síntesis química , Valina/química , Valina/farmacocinética , Proteínas no Estructurales Virales/metabolismoRESUMEN
In ongoing studies towards novel hepatitisâ C virus (HCV) therapeutics, inhibitors of nonstructural protein 5A (NS5A) were evaluated. Specifically, starting from previously reported lead compounds, peripheral substitution patterns of a series of biaryl-linked pyrrolidine NS5A replication complex inhibitors were probed and structure-activity relationships were elucidated. Using molecular modelling and a supercritical fluid chromatographic (SFC) technique, intramolecular H-bonding and peripheral functional group topology were evaluated as key determinants of activity and membrane permeability. The novel compounds exhibited retained potency as compared with the lead compounds, and also showed promising results against a panel of resistance viruses. Together, the results of the study take us a step closer towards understanding the potency of daclatasvir, a clinical candidate upon which the compounds were based, and to designing improved analogues as second-generation antiviral agents targeting NS5A.
Asunto(s)
Inhibidores de Proteasas/química , Proteínas no Estructurales Virales/antagonistas & inhibidores , Animales , Antivirales/síntesis química , Antivirales/química , Antivirales/farmacología , Línea Celular , Permeabilidad de la Membrana Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Perros , Evaluación Preclínica de Medicamentos , Farmacorresistencia Viral , Hepacivirus/metabolismo , Humanos , Enlace de Hidrógeno , Inhibidores de Proteasas/síntesis química , Inhibidores de Proteasas/farmacología , Ratas , Relación Estructura-Actividad , Proteínas no Estructurales Virales/metabolismo , Replicación Viral/efectos de los fármacosRESUMEN
UNLABELLED: Small molecule fluorometric boron dipyrromethene probes were developed to bind hepatitis C virus-encoded NS5A protein and aid subcellular distribution studies. These molecules did not co-locate with NS5A, therefore alternative 'silent' azide reporters were used to obtain a more relevant picture of their distribution. Following pre-incubation with replicon cells, click chemistry was used to append a fluorophore to the azide that confirmed the co-localisation of the small molecule with the NS5A protein, thus providing greater insight into the antiviral mode of action of this chemotype. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s12154-010-0047-1) contains supplementary material, which is available to authorized users.
RESUMEN
Owing to the polymorphic nature of CYP2D6, clinically significant issues can arise when drugs rely on that enzyme either for clearance, or metabolism to an active metabolite. Available screening methods to determine if the compound is likely to cause drug-drug interactions, or is likely to be a victim of inhibition of CYP2D6 by other compounds will be described. Computational models and examples will be given on strategies to design out the CYP2D6 liabilities for both heme-binding compounds and non-heme-binding compounds.
Asunto(s)
Citocromo P-450 CYP2D6/metabolismo , Interacciones Farmacológicas , Inhibidores Enzimáticos/farmacología , Animales , Biotransformación , Simulación por Computador , Diseño Asistido por Computadora , Citocromo P-450 CYP2D6/química , Citocromo P-450 CYP2D6/genética , Inhibidores del Citocromo P-450 CYP2D6 , Diseño de Fármacos , Inhibidores Enzimáticos/química , Hemo/metabolismo , Humanos , Modelos Moleculares , Estructura Molecular , Conformación Proteica , Relación Estructura-Actividad Cuantitativa , Medición de Riesgo , Especificidad por SustratoRESUMEN
A series of N-benzyl-N-(tetrahydro-2H-pyran-4-yl)pyrrolidin-3-amine monoamine reuptake inhibitors are described. Selective dual 5-HT and NA reuptake inhibition was achieved, and analogues with weak CYP2D6 inhibition, good human in vitro metabolic stability and wide ligand selectivity, such as 12b, were identified.
Asunto(s)
Química Farmacéutica/métodos , Inhibidores del Citocromo P-450 CYP2D6 , Norepinefrina/antagonistas & inhibidores , Pirrolidinas/síntesis química , Inhibidores Selectivos de la Recaptación de Serotonina/síntesis química , Aminas/química , Diseño de Fármacos , Canales de Potasio Éter-A-Go-Go/química , Hepatocitos/efectos de los fármacos , Hepatocitos/metabolismo , Humanos , Concentración 50 Inhibidora , Ligandos , Microsomas/efectos de los fármacos , Microsomas/metabolismo , Modelos Químicos , Conformación Molecular , Pirrolidinas/farmacología , Inhibidores Selectivos de la Recaptación de Serotonina/química , Inhibidores Selectivos de la Recaptación de Serotonina/farmacologíaRESUMEN
We report the structure-activity relationships of further analogues in a series of piperazine derivatives as dual inhibitors of serotonin and noradrenaline reuptake, that is, with additional substitution of the phenyl rings, or their replacement by heterocycles. The enantiomers of compounds 1 and 2 were also profiled, and possessed drug-like physicochemical properties. In particular, compound (-)-2 lacked potent inhibitory activity against any of the important cytochromes P(450) and high selectivity over a wide range of receptors, which is unusual for a compound that inhibits human amine transporters.
Asunto(s)
Piperazinas/química , Inhibidores Selectivos de la Recaptación de Serotonina/química , Inhibidores Selectivos de la Recaptación de Serotonina/farmacología , Aminas/química , Transporte Biológico , Línea Celular , Química Farmacéutica/métodos , Diseño de Fármacos , Humanos , Concentración 50 Inhibidora , Modelos Químicos , Piperazina , Piperazinas/farmacología , Proteínas de Transporte de Serotonina en la Membrana Plasmática/química , Relación Estructura-ActividadRESUMEN
The synthesis and structure-activity relationships of a novel series of piperazine derivatives as dual inhibitors of serotonin and noradrenaline reuptake is described. Two compounds possessed comparable in vitro profiles to the dual reuptake inhibitor duloxetine.