RESUMEN
Six novel 3â³-substituted (R)-N-(phenoxybenzyl) 2-N-acetamido-3-methoxypropionamides were prepared and then assessed using whole-cell, patch-clamp electrophysiology for their anticonvulsant activities in animal seizure models and for their sodium channel activities. We found compounds with various substituents at the terminal aromatic ring that had excellent anticonvulsant activity. Of these compounds, (R)-N-4'-((3â³-chloro)phenoxy)benzyl 2-N-acetamido-3-methoxypropionamide ((R)-5) and (R)-N-4'-((3â³-trifluoromethoxy)phenoxy)benzyl 2-N-acetamido-3-methoxypropionamide ((R)-9) exhibited high protective indices (PI=TD50/ED50) comparable with many antiseizure drugs when tested in the maximal electroshock seizure test to mice (intraperitoneally) and rats (intraperitoneally, orally). Most compounds potently transitioned sodium channels to the slow-inactivated state when evaluated in rat embryonic cortical neurons. Treating HEK293 recombinant cells that expressed hNaV1.1, rNaV1.3, hNaV1.5, or hNaV1.7 with (R)-9 recapitulated the high levels of sodium channel slow inactivation.
Asunto(s)
Acetamidas/síntesis química , Amidas/síntesis química , Aminoácidos/síntesis química , Anticonvulsivantes/síntesis química , Convulsiones/prevención & control , Bloqueadores del Canal de Sodio Activado por Voltaje/síntesis química , Canales de Sodio Activados por Voltaje/metabolismo , Acetamidas/farmacología , Administración Oral , Amidas/farmacología , Aminoácidos/farmacología , Animales , Anticonvulsivantes/farmacología , Corteza Cerebral/efectos de los fármacos , Corteza Cerebral/metabolismo , Corteza Cerebral/patología , Electrochoque , Células HEK293 , Humanos , Inyecciones Intraperitoneales , Masculino , Ratones , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Neuronas/patología , Técnicas de Placa-Clamp , Cultivo Primario de Células , Ratas , Ratas Sprague-Dawley , Convulsiones/metabolismo , Convulsiones/patología , Relación Estructura-Actividad , Bloqueadores del Canal de Sodio Activado por Voltaje/farmacologíaRESUMEN
We prepared 13 derivatives of N-(biphenyl-4'-yl)methyl (R)-2-acetamido-3-methoxypropionamide that differed in type and placement of a R-substituent in the terminal aryl unit. We demonstrated that the R-substituent impacted the compound's whole animal and cellular pharmacological activities. In rodents, select compounds exhibited excellent anticonvulsant activities and protective indices (PI=TD50/ED50) that compared favorably with clinical antiseizure drugs. Compounds with a polar, aprotic R-substituent potently promoted Na+ channel slow inactivation and displayed frequency (use) inhibition of Na+ currents at low micromolar concentrations. The possible advantage of affecting these two pathways to decrease neurological hyperexcitability is discussed.
Asunto(s)
Anticonvulsivantes/química , Anticonvulsivantes/farmacología , Compuestos de Bifenilo/farmacología , Convulsiones/tratamiento farmacológico , Serina/análogos & derivados , Bloqueadores de los Canales de Sodio/química , Bloqueadores de los Canales de Sodio/farmacología , Sodio/metabolismo , Animales , Anticonvulsivantes/administración & dosificación , Compuestos de Bifenilo/administración & dosificación , Compuestos de Bifenilo/química , Línea Celular Tumoral , Relación Dosis-Respuesta a Droga , Células HEK293 , Humanos , Masculino , Ratones , Estructura Molecular , Ratas , Ratas Sprague-Dawley , Serina/administración & dosificación , Serina/química , Serina/farmacología , Bloqueadores de los Canales de Sodio/administración & dosificación , Relación Estructura-ActividadRESUMEN
Benzyl esters of propiolic and beta-keto acids undergo catalytic decarboxylative coupling when treated with appropriate palladium catalysts. Such decarboxylative couplings allow the benzylation of alkynes without the use of strong bases and/or organometallics. This allows the synthesis of sensitive benzylic alkynes that are prone to undergo isomerizations under basic conditions. Additionally, decarboxylation facilitates the site-specific benzylation of diketones and ketoesters under mild, base-free conditions. Ultimately, the methodology described expands our ability to cross-couple medicinally relevant heterocycles.