RESUMEN
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
In an effort to develop orally active farnesoid X receptor (FXR) agonists, a series of tetrahydroazepinoindoles with appended solubilizing amine functionalities were synthesized. The crystal structure of the previously disclosed FXR agonist, 1 (FXR-450), aided in the design of compounds with tethered solubilizing functionalities designed to reach the solvent cavity around the hFXR receptor. These compounds were soluble in 0.5% methylcellulose/2% Tween-80 in water (MC/T) for oral administration. In vitro and in vivo optimization led to the identification of 14dd and 14cc, which in a dose-dependent fashion regulated low density lipoprotein cholesterol (LDLc) in low density lipoprotein receptor knockout (LDLR(-/-)) mice. Compound 14cc was dosed in female rhesus monkeys for 4 weeks at 60 mg/kg daily in MC/T vehicle. After 7 days, triglyceride (TG) levels and very low density lipoprotein cholesterol (VLDLc) levels were significantly decreased and LDLc was decreased 63%. These data are the first to demonstrate the dramatic lowering of serum LDLc levels by a FXR agonist in primates and supports the potential utility of 14cc in treating dyslipidemia in humans beyond just TG lowering.
Asunto(s)
Azepinas/síntesis química , Hipolipemiantes/síntesis química , Indoles/síntesis química , Receptores Citoplasmáticos y Nucleares/agonistas , Animales , Azepinas/farmacocinética , Azepinas/farmacología , Disponibilidad Biológica , Línea Celular , LDL-Colesterol/sangre , Femenino , Humanos , Hipolipemiantes/farmacocinética , Hipolipemiantes/farmacología , Indoles/farmacocinética , Indoles/farmacología , Macaca mulatta , Masculino , Ratones , Ratones Noqueados , Microsomas Hepáticos/metabolismo , Modelos Moleculares , Ratas , Ratas Sprague-Dawley , Receptores de LDL/genética , Solubilidad , Relación Estructura-Actividad , Triglicéridos/sangreRESUMEN
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
Pyrrole[2,3-d]azepines have been identified as potent agonists of the farnesoid X receptor (FXR). Based on the planar X-ray crystal structure of WAY-362450 1 in the ligand binding domain and molecular modeling studies, non-planar reduced compounds were designed which led to agonists that exhibit high aqueous solubility and retain moderate in vitro potency.
Asunto(s)
Azepinas/farmacología , Pirroles/farmacología , Receptores Citoplasmáticos y Nucleares/agonistas , Receptores Citoplasmáticos y Nucleares/metabolismo , Azepinas/química , Humanos , Modelos Moleculares , Unión Proteica , Pirroles/química , Receptores Citoplasmáticos y Nucleares/química , 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
Kv1.1 channels are expressed in many regions of the brain and spinal cord [Monaghan, M. M.; Trimmer, J. S.; Rhodes, K. J. J. Neurosci.2001, 21, 5973; Rasband, M. N.; Trimmer, J. S. J. Comp. Neurol.2001, 429, 166; Trimmer, J. S.; Rhodes, K. J. Ann. Rev. Physiol.2004, 66, 477]. When expressed alone, they produce a delayed rectifier slowly inactivating type current that contributes to hyperpolarizing the neuron following depolarization. In the hippocampus Kv1.1 is co-expressed with Kvbeta1 (and other beta subunits), which converts Kv1.1 into a transient, fast inactivating current, reducing its ability to hyperpolarize the cell and thus increasing neuronal excitability. To reduce neuronal excitability, screening for compounds that prevent inactivation of Kv1.1 channels by Kvbeta1 was performed using a yeast two-hybrid screen. A variety of compounds were discovered in this assay and subsequently determined to disrupt inactivation of the ionic currents, and hence were termed 'disinactivators'. Several of these disinactivators also inhibited pentylenetetrazole-induced seizures (PTZ) in mice. Compounds were found to act by several mechanisms to prevent Kvbeta1 inactivation of Kv1.1 channels, including enhancement of Ca(2+) release/influx and by direct mechanisms. Two structural classes were identified that act on a Kvbeta1N70-Kv1.1 chimera where the N-terminal 70 amino acids of Kvbeta1 were attached to the N-terminus of Kv1.1. It is likely that these disinactivators act directly on the Kvbeta1 N-terminus or its receptor site on Kv1.1, thus preventing it from blocking Kv1.1 channels. Compounds acting by this mechanism may be useful for reducing neuronal hyperexcitability in diseases such as epilepsy and neuropathic pain.