RESUMEN
A series of pyrrolo-benzo-1,4-diazine analogs have been synthesized and displayed potent Nav1.7 inhibitory activity and moderate selectivity over Nav1.5. The syntheses, structure-activity relationships, and selected pharmacokinetic data of these analogs are described. Compound 41 displayed anti-nociceptive efficacy in the rat CFA pain model at 100 mpk oral dosing.
Asunto(s)
Descubrimiento de Drogas , Canal de Sodio Activado por Voltaje NAV1.7/metabolismo , Quinoxalinas/farmacología , Bloqueadores de los Canales de Sodio/farmacología , Compuestos de Espiro/farmacología , Relación Dosis-Respuesta a Droga , Humanos , Estructura Molecular , Quinoxalinas/síntesis química , Quinoxalinas/química , Bloqueadores de los Canales de Sodio/síntesis química , Bloqueadores de los Canales de Sodio/química , Compuestos de Espiro/síntesis química , Compuestos de Espiro/química , Relación Estructura-ActividadRESUMEN
Serotonin type 3 (5-HT3) receptor partial agonists have been targeted as potential new drugs for the symptomatic relief of irritable bowel syndrome (IBS). Multiple diazepinone-based compounds have been discovered, which exhibit nanomolar binding affinity for the h5-HT3A receptor and display a range of intrinsic activities (IA=7-87% of 5-HT Emax) in HEK cells heterologously expressing the h5-HT3A receptor. Favorable physicochemical properties and in vitro ADME profile coupled with oral activity in the murine von Bezold-Jarisch reflex model demonstrates the series has promise for producing low to moderate IA partial agonists suitable for an IBS indication.
Asunto(s)
Azepinas/farmacología , Descubrimiento de Drogas , Síndrome del Colon Irritable/tratamiento farmacológico , Receptores de Serotonina 5-HT3/metabolismo , Administración Oral , Animales , Azepinas/administración & dosificación , Azepinas/química , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Células HEK293 , Humanos , Ratones , Estructura Molecular , Relación Estructura-ActividadRESUMEN
Serotonin type 3 (5-HT(3)) receptor partial agonists are being targeted as potential new drugs for the treatment of irritable bowel syndrome (IBS). Two new chemical series bearing indazole and indole cores have exhibited nanomolar binding affinity for the h5-HT(3)A receptor. A range of partial agonist activities in HEK cells heterologously expressing the h5-HT(3)A receptor were measured for the indazole series. Excellent 5-HT(3) receptor selectivity, favorable in vitro metabolic stability and CYP inhibition properties, and good oral in vivo potency in the murine von Bezold-Jarisch reflex model is exemplified thereby indicating the series to have potential utility as improved IBS agents.
Asunto(s)
Síndrome del Colon Irritable/tratamiento farmacológico , Receptores de Serotonina 5-HT3/química , Agonistas del Receptor de Serotonina 5-HT3/química , Animales , Línea Celular , Modelos Animales de Enfermedad , Humanos , Imidazoles/química , Indoles/química , Ratones , Microsomas Hepáticos/metabolismo , Receptores de Serotonina 5-HT3/metabolismo , Agonistas del Receptor de Serotonina 5-HT3/síntesis química , Agonistas del Receptor de Serotonina 5-HT3/uso terapéuticoRESUMEN
A highly efficient procedure was developed for the microwave-assisted synthesis of N-heteroaryl-4-(2-chloroethyl)piperazines and N-heteroaryl-4-(2-chloroethyl)piperidines. Microwave irradiation of electron deficient heteroaryl chlorides with 1,4-diazabicyclo[2.2.2]octane (DABCO) at 160 degrees C for 15 min led to N-heteroaryl-4-(2-chloroethyl)piperazines in good to excellent yields. In a similar manner, microwave irradiation of electron deficient heteroaryl chlorides with quinuclidine at 180 degrees C for 15 min provided N-heteroaryl-4-(2-chloroethyl)piperidines in good to excellent yields. Extension of the method was demonstrated by the development of a one-pot, two-step microwave-assisted protocol for the synthesis of 4-(2-acetoxyethyl)-substituted N-heteroarylpiperazines and N-heteroarylpiperidines to demonstrate the production of a small library in a parallel fashion.
Asunto(s)
Aminas/química , Cloruros/química , Piperazinas/síntesis química , Piperidinas/síntesis química , Bibliotecas de Moléculas Pequeñas/síntesis química , Aminas/síntesis química , Cloruros/síntesis química , Microondas , Piperazinas/química , Piperidinas/química , Quinuclidinas/síntesis química , Quinuclidinas/química , Bibliotecas de Moléculas Pequeñas/química , Bibliotecas de Moléculas Pequeñas/economíaRESUMEN
An efficient and rapid solution phase combinatorial synthesis of a 3-substituted 5-arylidene-1-methyl-2-thiohydantoin library was developed. The salient feature for this library production procedure is the addition of the Lewis acid catalyst, indium(III) trifluoromethanesulfonate, which serves to facilitate the direct condensation of aldehydes with 3-substituted 1-methyl-2-thiohydantoins. Use of this Lewis acid catalyst has resulted in faster reaction times, higher conversions and better purity profiles for these condensation reactions as compared to traditional uncatalyzed reactions. The resulting 315 member library of 3-substituted 5-arylidene-1-methyl-2-thiohydantoin is described.
Asunto(s)
Compuestos Organometálicos/química , Tiohidantoínas/síntesis química , Aldehídos/química , Catálisis , Modelos QuímicosRESUMEN
A detailed examination of the use of aza-Cope rearrangement-Mannich cyclization sequences for assembling the azatricyclo[4.4.0.0(2,8)]decane core of gelsemine is described. Iminium ions and N-acyloxyiminium ions derived from endo-oriented 1-methoxy- or 1-hydroxybicyclo[2.2.2]oct-5-enylamines do not undergo the first step of this sequence, cationic aza-Cope rearrangement, to form cis-hydroisoquinolinium ions. However, the analogous base-promoted oxy-aza-Cope rearrangement does take place to form cis-hydroisoquinolones containing functionality that allows iminium ions or N-acyloxyiminium ions to be generated regioselectively in a subsequent step. Mannich cyclization of cis-hydroisoquinolones prepared in this way efficiently assembles the azatricyclo[4.4.0.0(2,8)]decane unit of gelsemine. Using a sequential base-promoted oxy-aza-Cope rearrangement/Mannich cyclization sequence, gram quantities of azatricyclo[4.4.0.0(2,8)]decanone 18, a central intermediate in our total of (+/-)-gelsemine, were prepared from 3-methylanisole in 12 steps and 16% overall yield.