RESUMEN
Sequential modification of the previously identified 4-[3-aryl-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-1-(methylamino)butan-2-ols led to the identification of a new series of 1-(2-morpholin-2-ylethyl)-3-aryl-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxides that are potent and selective inhibitors of the norepinephrine transporter over both the serotonin and dopamine transporters. One representative compound 10b (WYE-114152) had low nanomolar hNET potency (IC(50) = 15 nM) and good selectivity for hNET over hSERT (>430-fold) and hDAT (>548-fold). 10b was additionally bioavailable following oral dosing and demonstrated efficacy in rat models of acute, inflammatory, and neuropathic pain.
Asunto(s)
Analgésicos/síntesis química , Benzotiazoles/síntesis química , Óxidos S-Cíclicos/síntesis química , Morfolinas/síntesis química , Proteínas de Transporte de Noradrenalina a través de la Membrana Plasmática/antagonistas & inhibidores , Tiadiazoles/síntesis química , Dolor Agudo/tratamiento farmacológico , Administración Oral , Analgésicos/química , Analgésicos/farmacología , Animales , Benzotiazoles/química , Benzotiazoles/farmacología , Disponibilidad Biológica , Línea Celular , Dolor Crónico/tratamiento farmacológico , Cricetinae , Óxidos S-Cíclicos/química , Óxidos S-Cíclicos/farmacología , Perros , Humanos , Inflamación/tratamiento farmacológico , Inflamación/fisiopatología , Inyecciones Intravenosas , Masculino , Morfolinas/química , Morfolinas/farmacología , Neuralgia/tratamiento farmacológico , Ratas , Estereoisomerismo , Tiadiazoles/química , Tiadiazoles/farmacologíaRESUMEN
Non-steroidal 1-methyl-1H-pyrrole-2-carbonitrile containing tetrahydronaphthalenes and acyclic derivatives were evaluated as novel series of progesterone receptor (PR) antagonists using the T47D cell alkaline phosphatase assay. Moderate to potent PR antagonists were achieved with these scaffolds. Several compounds (e.g., 15 and 20) demonstrated low nanomolar PR antagonist potency and good selectivity versus other steroid receptors.
Asunto(s)
Pirroles/química , Receptores de Progesterona/antagonistas & inhibidores , Tetrahidronaftalenos/química , Fosfatasa Alcalina/metabolismo , Línea Celular Tumoral , Humanos , Receptores de Progesterona/metabolismo , Relación Estructura-Actividad , Tetrahidronaftalenos/síntesis química , Tetrahidronaftalenos/farmacologíaRESUMEN
Structural modification of a virtual screening hit led to the identification of a new series of 4-[3-aryl-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-1-(methylamino)butan-2-ols which are potent and selective inhibitors of the norepinephrine transporter over both the serotonin and dopamine transporters. One representative compound S-17b (WYE-103231) had low nanomolar hNET potency (IC(50) = 1.2 nM) and excellent selectivity for hNET over hSERT (>1600-fold) and hDAT (>600-fold). S-17b additionally had a good pharmacokinetic profile and demonstrated oral efficacy in rat models of ovariectomized-induced thermoregulatory dysfunction and morphine dependent flush as well as the hot plate and spinal nerve ligation (SNL) models of acute and neuropathic pain.
Asunto(s)
Óxidos S-Cíclicos/química , Óxidos S-Cíclicos/farmacología , Descubrimiento de Drogas/métodos , Inhibidores de la Captación de Neurotransmisores/química , Inhibidores de la Captación de Neurotransmisores/farmacología , Norepinefrina/metabolismo , Tiadiazoles/química , Tiadiazoles/farmacología , Animales , Línea Celular , Óxidos S-Cíclicos/síntesis química , Óxidos S-Cíclicos/farmacocinética , Femenino , Humanos , Masculino , Inhibidores de la Captación de Neurotransmisores/síntesis química , Inhibidores de la Captación de Neurotransmisores/farmacocinética , Ratas , Relación Estructura-Actividad , Tiadiazoles/síntesis química , Tiadiazoles/farmacocinéticaRESUMEN
A series of biaryl amides containing an azabicyclooctane amine headpiece were synthesized and evaluated as mixed arginine vasopressin (AVP) receptor antagonists. Several analogues, including 8g, 12g, 13d, and 13g, were shown to have excellent V(1a)- and good V(2)-receptor binding affinities. Compound 13d was further profiled for drug-like properties and for an in vitro comparison with conivaptan, the program's mixed V(1a)/V(2)-receptor antagonist standard.
Asunto(s)
Antagonistas de los Receptores de Hormonas Antidiuréticas , Arginina Vasopresina/antagonistas & inhibidores , Compuestos Aza/síntesis química , Compuestos Bicíclicos con Puentes/síntesis química , Octanos/síntesis química , Animales , Compuestos Aza/farmacología , Benzazepinas , Compuestos Bicíclicos con Puentes/farmacología , Humanos , Estructura Molecular , Octanos/farmacología , Relación Estructura-ActividadRESUMEN
A series of heterocyclic cycloalkanol ethylamines have been prepared to expand our norepinephrine reuptake inhibitor (NRI) program. Synthesis of a variety of heterocycles identified (+)-S-21, a potent NRI efficacious in an animal model for thermoregulatory dysfunction.
Asunto(s)
Etilaminas/química , Inhibidores de la Captación de Neurotransmisores/química , Norepinefrina/metabolismo , Piperazinas/química , Tiofenos/química , Animales , Cristalografía por Rayos X , Etilaminas/síntesis química , Etilaminas/farmacología , Humanos , Conformación Molecular , Inhibidores de la Captación de Neurotransmisores/síntesis química , Inhibidores de la Captación de Neurotransmisores/farmacología , Norepinefrina/química , Piperazinas/síntesis química , Piperazinas/farmacología , Ratas , Relación Estructura-Actividad , Tiofenos/síntesis química , Tiofenos/farmacologíaRESUMEN
Efforts to identify new selective and potent norepinephrine reuptake inhibitors (NRIs) for multiple indications by structural modification of the previous 3-(arylamino)-3-phenylpropan-2-olamine scaffold led to the discovery of a novel series of 1-(indolin-1-yl)-1-phenyl-3-propan-2-olamines (9). Investigation of the structure-activity relationships revealed that small alkyl substitution at the C3 position of the indoline ring enhanced selectivity for the norepinephrine transporter (NET) over the serotonin transporter (SERT). Several compounds bearing a 3,3-dimethyl group on the indoline ring, 9k, 9o,p, and 9s,t, exhibited potent inhibition of NET (IC(50) = 2.7-6.5 nM) and excellent selectivity over both serotonin and dopamine transporters. The best example from this series, 9p, a potent and highly selective NRI, displayed oral efficacy in a telemetric rat model of ovariectomized-induced thermoregulatory dysfunction, a mouse p-phenylquinone (PPQ) model of acute visceral pain, and a rat spinal nerve ligation (SNL) model of neuropathic pain.
Asunto(s)
Indoles/farmacología , Inhibidores de la Captación de Neurotransmisores/química , Inhibidores de la Captación de Neurotransmisores/farmacología , Proteínas de Transporte de Noradrenalina a través de la Membrana Plasmática/antagonistas & inhibidores , Propanolaminas/farmacología , Animales , Regulación de la Temperatura Corporal/efectos de los fármacos , Femenino , Indoles/síntesis química , Indoles/química , Espectroscopía de Resonancia Magnética , Inhibidores de la Captación de Neurotransmisores/síntesis química , Proteínas de Transporte de Noradrenalina a través de la Membrana Plasmática/metabolismo , Dolor/tratamiento farmacológico , Propanolaminas/síntesis química , Propanolaminas/química , Ratas , Espectrometría de Masa por Ionización de Electrospray , Relación Estructura-ActividadRESUMEN
Two related series of selective norepinephrine reuptake inhibitors were synthesized based on 3,4-dihydro-1H-2,1,3-benzothiadiazine 2,2-dioxide or 3,4-dihydrosulfostyril cores, and screened for monoamine reuptake inhibition. Structure-activity relationships were determined for the series' in vitro potency and selectivity versus serotonin or dopamine transporter inhibition, and analogs based on both cores were identified as potent and selective NRIs. The 3,4-dihydrosulfostyril series was further tested for microsome stability, and compound 16j, which was optimized for both potency and stability, showed efficacy in an in vivo model of thermoregulatory dysfunction.
Asunto(s)
Inhibidores de Captación Adrenérgica/química , Benzotiadiazinas/química , Óxidos S-Cíclicos/química , Proteínas de Transporte de Noradrenalina a través de la Membrana Plasmática/química , Norepinefrina/metabolismo , Tiazinas/química , Inhibidores de Captación Adrenérgica/síntesis química , Inhibidores de Captación Adrenérgica/farmacología , Animales , Transporte Biológico , Óxidos S-Cíclicos/síntesis química , Óxidos S-Cíclicos/farmacología , Humanos , Microsomas Hepáticos/metabolismo , Modelos Animales , Proteínas de Transporte de Noradrenalina a través de la Membrana Plasmática/metabolismo , Ratas , Relación Estructura-Actividad , Tiazinas/síntesis química , Tiazinas/farmacologíaRESUMEN
Piperidinyl diphenylsulfonyl sulfonamides are a novel class of molecules that have inhibitory binding affinity for sFRP-1. As a secreted protein sFRP-1 inhibits the function of the secreted Wnt glycoprotein. Therefore, as inhibitors of sFRP-1 these small molecules facilitate the Wnt/beta-catenin canonical signaling pathway. Details of the structure-activity relationships and biological activity of this structural class of compounds will be discussed.
Asunto(s)
Glicoproteínas/antagonistas & inhibidores , Transducción de Señal/efectos de los fármacos , Sulfonamidas/química , Sulfonamidas/farmacología , Proteínas Wnt/metabolismo , Animales , Línea Celular Tumoral , Glicoproteínas/metabolismo , Humanos , Péptidos y Proteínas de Señalización Intracelular , Ratones , Microsomas Hepáticos/metabolismo , Técnicas de Cultivo de Órganos , Osteogénesis/efectos de los fármacos , Ratas , Cráneo/citología , Cráneo/efectos de los fármacos , Relación Estructura-Actividad , beta Catenina/metabolismoRESUMEN
The potency and selectivity of a series of 1-{(1S)-2-[amino]-1-[3-(trifluoromethoxy)phenyl]ethyl}cyclohexanol analogues are described. These compounds were prepared to improve in vitro metabolic stability and achieve brain penetration. Compound 13 (WAY-260022, NRI-022) was found to be a potent inhibitor of norepinephrine reuptake and demonstrated excellent selectivity over the serotonin and dopamine transporters. Additionally, 13 exhibited oral efficacy in a rat model of thermoregulatory dysfunction.
RESUMEN
Atrial fibrillation is the most prevalent form of cardiac arrhythmia. Current treatments extend the atrial effective refractory period by nonselective blockade of cardiac ion channels. An alternative approach selectively targeting the Kv1.5 ion channel offers the opportunity for therapeutic benefit with decreased risk of adverse cardiovascular events. KVI-020 (4g) successfully demonstrated antiarrhythmic efficacy in a canine arrhythmia model, and these findings support its utility as an antiarrhythmic agent.
Asunto(s)
Antiarrítmicos/síntesis química , Fibrilación Atrial/tratamiento farmacológico , Imidazolidinas/síntesis química , Canal de Potasio Kv1.5/antagonistas & inhibidores , Sulfonamidas/síntesis química , Animales , Antiarrítmicos/farmacocinética , Antiarrítmicos/farmacología , Línea Celular , Cricetinae , Cricetulus , Perros , Humanos , Imidazolidinas/farmacocinética , Imidazolidinas/farmacología , Técnicas In Vitro , Microsomas Hepáticos/metabolismo , Técnicas de Placa-Clamp , Solubilidad , Estereoisomerismo , Relación Estructura-Actividad , Sulfonamidas/farmacocinética , Sulfonamidas/farmacologíaRESUMEN
Novel 5-aryl indanones, inden-1-one oximes, and inden-1-ols were synthesized and evaluated as progesterone receptor (PR) modulators using the T47D cell alkaline phosphatase assay. Both PR agonists and antagonists were achieved with appropriate 3- and 5-substitution from indanones and inden-1-ols while inden-1-one oximes provided only PR antagonists. Several compounds such as 10 and 11 demonstrated potent in vitro PR agonist potency similar to that of steroidal progesterone (1). In addition, a number of compounds (e.g., 12, 13, 17, 18) showed potent PR antagonist activity indicating the indanones and derivatives are promising PR modulator templates.
Asunto(s)
Indanos/farmacología , Receptores de Progesterona/agonistas , Receptores de Progesterona/antagonistas & inhibidores , Diseño de Fármacos , Indanos/síntesis química , Indanos/química , Estructura Molecular , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
The discovery of a series of 4-aminoethyl-3-(phenylsulfonyl)-1H-indoles, dual acting norepinephrine reuptake inhibitors (NRIs) and 5-HT(2A) receptor antagonists, is described. The synthesis and structure-activity relationship (SAR) of this novel series of compounds is also presented.
Asunto(s)
Indoles/farmacología , Inhibidores de la Captación de Neurotransmisores/síntesis química , Inhibidores de la Captación de Neurotransmisores/farmacología , Norepinefrina/metabolismo , Antagonistas del Receptor de Serotonina 5-HT2 , Antagonistas de la Serotonina/síntesis química , Antagonistas de la Serotonina/farmacología , Transporte Biológico/efectos de los fármacos , Línea Celular , Humanos , Indoles/síntesis química , Indoles/metabolismo , Inhibidores de la Captación de Neurotransmisores/metabolismo , Receptor de Serotonina 5-HT2A/metabolismo , Antagonistas de la Serotonina/metabolismo , Relación Estructura-ActividadRESUMEN
Sequential structural modifications of the aryloxypropanamine template (e.g., atomoxetine, 2) led to a novel series of 1-(3-amino-2-hydroxy-1-phenyl propyl)-1,3-dihydro-2H-benzimidazol-2-ones as selective norepinephrine reuptake inhibitors (NRIs). In general, this series of compounds potently blocked the human norepinephrine transporter (hNET) while exhibiting selectivity at hNET against both the human serotonin (hSERT) and dopamine transporters (hDAT). Numerous compounds (e.g., 19-22) had low nonamolar hNET potency with IC(50) values of 7-10 nM and excellent selectivity (>500 fold) at hNET over hSERT and hDAT. Several compounds, such as 20 and 22, were tested in a telemetric rat model of ovariectomized-induced thermoregulatory dysfunction and were efficacious at oral doses of 3 mg/kg in reducing the tail skin temperature. In addition, compound 20 was also studied in the rat hot plate and spinal nerve ligation (SNL) models of acute and neuropathic pain, respectively, and was orally efficacious at doses of 3-10 mg/kg.
Asunto(s)
Bencimidazoles/química , Bencimidazoles/farmacología , Inhibidores de la Captación de Neurotransmisores/química , Inhibidores de la Captación de Neurotransmisores/farmacología , Norepinefrina/metabolismo , Administración Oral , Animales , Conducta Animal/efectos de los fármacos , Bencimidazoles/administración & dosificación , Bencimidazoles/farmacocinética , Transporte Biológico/efectos de los fármacos , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/antagonistas & inhibidores , Femenino , Humanos , Hiperalgesia/fisiopatología , Masculino , Inhibidores de la Captación de Neurotransmisores/administración & dosificación , Inhibidores de la Captación de Neurotransmisores/farmacocinética , Proteínas de Transporte de Noradrenalina a través de la Membrana Plasmática/antagonistas & inhibidores , Propanolaminas/química , Ratas , Ratas Sprague-Dawley , Proteínas de Transporte de Serotonina en la Membrana Plasmática/metabolismo , Nervios Espinales/efectos de los fármacos , Nervios Espinales/fisiología , Relación Estructura-Actividad , Especificidad por SustratoRESUMEN
The SAR of a series of 1-amino-3-(1H-indol-1-yl)-3-phenylpropan-2-ols as monoamine reuptake inhibitors, with a goal to improve both potency toward inhibiting the norepinephrine transporter and selectivity over the serotonin transporter, is reported. The effect of specific substitution on both the 3-phenyl group and the indole moiety were explored. This study led to the discovery of compound 20 which inhibited the norepinephrine transporter with an IC50 value of 4 nM while exhibiting 86-fold selectivity over the serotonin transporter.
Asunto(s)
Inhibidores de Captación Adrenérgica/química , Indoles/química , Proteínas de Transporte de Noradrenalina a través de la Membrana Plasmática/antagonistas & inhibidores , Inhibidores de Captación Adrenérgica/síntesis química , Inhibidores de Captación Adrenérgica/farmacocinética , Animales , Humanos , Indoles/síntesis química , Indoles/farmacocinética , Modelos Animales , Proteínas de Transporte de Noradrenalina a través de la Membrana Plasmática/metabolismo , Ratas , Proteínas de Transporte de Serotonina en la Membrana Plasmática/química , 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/química , Inhibidores Selectivos de la Recaptación de Serotonina/farmacocinética , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
A novel series of monoamine reuptake inhibitors, the 1-amino-3-(1H-indol-1-yl)-3-phenylpropan-2-ols, have been discovered by combining virtual and focused screening efforts with design techniques. Synthesis of the two diastereomeric isomers of the molecule followed by chiral resolution of each enantiomer revealed the (2R,3S)-isomer to be a potent norepinephrine reuptake inhibitor (IC(50)=28 nM) with excellent selectivity over the dopamine transporter and 13-fold selectivity over the serotonin transporter.
Asunto(s)
Inhibidores de Captación Adrenérgica/química , Antidepresivos/química , Norepinefrina/antagonistas & inhibidores , Propanoles/química , Inhibidores de Captación Adrenérgica/síntesis química , Inhibidores de Captación Adrenérgica/farmacología , Animales , Antidepresivos/síntesis química , Antidepresivos/farmacología , Células CHO , Línea Celular , Cricetinae , Cricetulus , Cristalografía por Rayos X , Perros , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/antagonistas & inhibidores , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/metabolismo , Descubrimiento de Drogas , Humanos , Conformación Molecular , Propanoles/síntesis química , Propanoles/farmacología , Proteínas Recombinantes/antagonistas & inhibidores , Proteínas Recombinantes/metabolismo , Proteínas de Transporte de Serotonina en la Membrana Plasmática/metabolismo , Relación Estructura-ActividadRESUMEN
A series of 3-(arylamino)-3-phenylpropan-2-olamines was prepared and screened for their ability to inhibit monoamine reuptake. A number of analogues displayed significant dual norepinephrine and serotonin reuptake inhibition. Compounds in this class exhibited minimal affinity for the dopamine transporter.
Asunto(s)
Química Farmacéutica/métodos , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/antagonistas & inhibidores , Norepinefrina/antagonistas & inhibidores , Propanolaminas/síntesis química , Inhibidores Selectivos de la Recaptación de Serotonina/síntesis química , Inhibidores de Captación Adrenérgica/farmacología , Animales , Perros , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/química , Diseño de Fármacos , Humanos , Concentración 50 Inhibidora , Ligandos , Modelos Químicos , Propanolaminas/farmacología , Inhibidores Selectivos de la Recaptación de Serotonina/farmacología , Relación Estructura-ActividadRESUMEN
Canonical Wnt signaling has been demonstrated to increase bone formation, and Wnt pathway components are being pursued as potential drug targets for osteoporosis and other metabolic bone diseases. Deletion of the Wnt antagonist secreted frizzled-related protein (sFRP)-1 in mice activates canonical signaling in bone and increases trabecular bone formation in aged animals. We have developed small molecules that bind to and inhibit sFRP-1 in vitro and demonstrate robust anabolic activity in an ex vivo organ culture assay. A library of over 440,000 drug-like compounds was screened for inhibitors of human sFRP-1 using a cell-based functional assay that measured activation of canonical Wnt signaling with an optimized T-cell factor (TCF)-luciferase reporter gene assay. One of the hits in this screen, a diarylsulfone sulfonamide, bound to sFRP-1 with a K(D) of 0.35 microM in a tryptophan fluorescence quenching assay. This compound also selectively inhibited sFRP-1 with an EC(50) of 3.9 microM in the cell-based functional assay. Optimization of this high throughput screening hit for binding and functional potency as well as metabolic stability and other pharmaceutical properties led to improved lead compounds. One of these leads (WAY-316606) bound to sFRP-1 with a K(D) of 0.08 microM and inhibited it with an EC(50) of 0.65 microM. Moreover, this compound increased total bone area in a murine calvarial organ culture assay at concentrations as low as 0.0001 microM. This work demonstrates the feasibility of developing small molecules that inhibit sFRP-1 and stimulate canonical Wnt signaling to increase bone formation.
Asunto(s)
Osteogénesis/efectos de los fármacos , Proteínas/antagonistas & inhibidores , Sulfonamidas/farmacología , Proteínas Wnt/antagonistas & inhibidores , Animales , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Humanos , Péptidos y Proteínas de Señalización Intracelular , Ratones , Técnicas de Cultivo de Órganos , Osteoblastos/citología , Osteoblastos/efectos de los fármacos , Osteocitos/citología , Osteocitos/efectos de los fármacos , Proteínas/genética , Proteínas/metabolismo , Cráneo/citología , Cráneo/efectos de los fármacos , Espectrometría de Fluorescencia , Sulfonamidas/químicaRESUMEN
The diphenylsulfonyl sulfonamide scaffold represented by 1 (WAY-316606) are small molecule inhibitors of the secreted protein sFRP-1, an endogenous antagonist of the secreted glycoprotein Wnt. Modulators of the Wnt pathway have been proposed as anabolic agents for the treatment of osteoporosis or other bone-related disorders. Details of the structure-activity relationships and biological activity from the first structural class of this scaffold will be discussed.
Asunto(s)
Piperidinas/química , Proteínas/antagonistas & inhibidores , Proteínas/metabolismo , Transducción de Señal/efectos de los fármacos , Sulfanilamidas/síntesis química , Sulfanilamidas/farmacología , Proteínas Wnt/metabolismo , Animales , Línea Celular Tumoral , Genes Reporteros/genética , Humanos , Concentración 50 Inhibidora , Péptidos y Proteínas de Señalización Intracelular , Isomerismo , Ratones , Estructura Molecular , Unión Proteica , Cráneo/efectos de los fármacos , Relación Estructura-Actividad , Sulfanilamidas/química , Proteínas Wnt/genéticaRESUMEN
A series of novel 1- or 3-(3-amino-1-phenyl propyl)-1,3-dihydro-2H-benzimidazol-2-ones as selective norepinephrine reuptake inhibitors was discovered. Several compounds such as 15 and 20 showed good hNET potency. Compounds 15 and 20 also displayed excellent selectivity at hNET that appeared superior to those of reboxetine and atomoxetine (4 and 5).
Asunto(s)
Bencimidazoles/síntesis química , Bencimidazoles/farmacología , Inhibidores de la Captación de Neurotransmisores/síntesis química , Inhibidores de la Captación de Neurotransmisores/farmacología , Norepinefrina/antagonistas & inhibidores , Bencimidazoles/química , Técnicas Químicas Combinatorias , Diseño de Fármacos , Humanos , Estructura Molecular , Inhibidores de la Captación de Neurotransmisores/química , Norepinefrina/metabolismo , EstereoisomerismoRESUMEN
Norepinephrine and serotonin play an important role in a wide variety of biological processes and are implicated in a number of neurological disorders. A novel class of 1-(3-amino-1-phenylpropyl)indolin-2-ones was designed and synthesized that displays potent norepinephrine reuptake inhibition while maintaining high selectivity (>100-fold) against the human serotonin and dopamine transporters.