RESUMEN
A series of oxadiazolone bioisosteres of pregabalin 1 and gabapentin 2 were prepared, and several were found to exhibit similar potency for the alpha(2)-delta subunit of voltage-gated calcium channels. Oxadiazolone 9 derived from 2 achieved low brain uptake but was nevertheless active in models of osteoarthritis. The high clearance associated with compound 9 was postulated to be a consequence of efflux by OAT and/or OCT, and was attenuated on co-administration with cimetidine or probenecid.
Asunto(s)
Aminas , Ácidos Ciclohexanocarboxílicos , Osteoartritis/tratamiento farmacológico , Oxadiazoles/química , Oxadiazoles/uso terapéutico , Ácido gamma-Aminobutírico/análogos & derivados , Animales , Encéfalo/metabolismo , Interacciones Farmacológicas , Quimioterapia Combinada , Gabapentina , Factores de Transcripción de Octámeros , Transportadores de Anión Orgánico , Oxadiazoles/farmacología , Pregabalina , RatasRESUMEN
Several beta-amino tetrazole analogs of gabapentin 1 and pregabalin 2 were prepared by one of two convergent, highly efficient routes, and their affinity for the alpha(2)-delta protein examined. Two select compounds with potent affinity for alpha(2)-delta, 8a and 16a, were subsequently tested in vivo in an audiogenic seizure model and found to elicit protective effects.
Asunto(s)
Anticonvulsivantes/síntesis química , Anticonvulsivantes/farmacología , Ácidos Carboxílicos/química , Epilepsia Refleja/prevención & control , Ácido gamma-Aminobutírico/análogos & derivados , Aminas/síntesis química , Aminas/química , Aminas/farmacología , Animales , Anticonvulsivantes/química , Sitios de Unión , Ácidos Ciclohexanocarboxílicos/síntesis química , Ácidos Ciclohexanocarboxílicos/química , Ácidos Ciclohexanocarboxílicos/farmacología , Modelos Animales de Enfermedad , Evaluación Preclínica de Medicamentos , Gabapentina , Ratones , Ratones Endogámicos DBA , Estructura Molecular , Pregabalina , Subunidades de Proteína/efectos de los fármacos , Estereoisomerismo , Relación Estructura-Actividad , Ácido gamma-Aminobutírico/síntesis química , Ácido gamma-Aminobutírico/química , Ácido gamma-Aminobutírico/farmacologíaRESUMEN
A series of carboxylate bioisosteres of structures related to gabapentin 1 have been prepared. When the carboxylate was replaced by a tetrazole, this group was recognized by the alpha2-delta protein. Further characterization of alpha2-delta binding compounds 14a and 14b revealed a similar pattern of functional in vitro and in vivo activity to gabapentin 1.
Asunto(s)
Aminas/síntesis química , Aminas/farmacología , Anticonvulsivantes/química , Anticonvulsivantes/farmacología , Ácidos Carboxílicos/química , Ácidos Ciclohexanocarboxílicos/síntesis química , Ácidos Ciclohexanocarboxílicos/farmacología , Tetrazoles/química , Ácido gamma-Aminobutírico/síntesis química , Ácido gamma-Aminobutírico/farmacología , Aminas/química , Animales , Anticonvulsivantes/síntesis química , Ácidos Ciclohexanocarboxílicos/química , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Diseño de Fármacos , Evaluación Preclínica de Medicamentos , Gabapentina , Técnicas In Vitro , Ratones , Ratones Endogámicos DBA , Estructura Molecular , Ratas , Estereoisomerismo , Relación Estructura-Actividad , Ácido gamma-Aminobutírico/químicaRESUMEN
A series of heteroaromatic analogs of pregabalin has been identified that possess anticonvulsant activity in the DBA/2 mouse model. The methods of synthesis and preliminary pharmacology are discussed herein.
Asunto(s)
Anticonvulsivantes/química , Anticonvulsivantes/farmacología , Convulsiones/prevención & control , Ácido gamma-Aminobutírico/análogos & derivados , Animales , Anticonvulsivantes/síntesis química , Modelos Animales de Enfermedad , Diseño de Fármacos , Evaluación Preclínica de Medicamentos , Técnicas In Vitro , Ratones , Ratones Endogámicos DBA , Estructura Molecular , Pregabalina , Estereoisomerismo , Ácido gamma-Aminobutírico/síntesis química , Ácido gamma-Aminobutírico/química , Ácido gamma-Aminobutírico/farmacologíaRESUMEN
Pregabalin (Lyrica) is a novel amino acid compound that binds with high affinity to the alpha2-delta (alpha2-delta) auxiliary protein of voltage-gated calcium channels. In vivo, it potently prevents seizures, pain-related behaviors and has anxiolytic-like activity in rodent models. The present studies were performed to determine the profile of pregabalin anticonvulsant activity in a variety of mouse and rat models. In the high-intensity electroshock test, pregabalin potently inhibited tonic extensor seizures in rats (ED50 = 1.8 mg/kg, PO), and low-intensity electroshock seizures in mice. It prevented tonic extensor seizures in the DBA/2 audiogenic mouse model (ED50 = 2.7 mg/kg, PO). Its time course of action against electroshock induced seizures in rats roughly followed the pharmacokinetics of radiolabeled drug in the brain compartment. At higher dosages (ED50 1= 31 mg/kg, PO), pregabalin prevented clonic seizures from pentylenetetrazole in mice. In a kindled rat model of partial seizures, pregabalin prevented stages 4-5 behavioral seizures (lowest effective dose = 10 mg/kg, IP), and also reduced the duration of electrographic seizures. Pregabalin was not active to prevent spontaneous absence-like seizures in the Genetic Absence Epilepsy in Rats from Strasbourg (GAERS) inbred Wistar rat strain. Pregabalin caused ataxia and decreased spontaneous locomotor activity at dosages 10-30-fold higher than those active to prevent seizures. These findings suggest that pregabalin has an anticonvulsant mechanism different from the prototype antiepileptic drugs and similar to that of gabapentin except with increased potency and bioavailability. In summary, our results show that pregabalin has several properties that favor treatment of partial seizures in humans.
Asunto(s)
Anticonvulsivantes/farmacocinética , Conducta Animal/efectos de los fármacos , Epilepsia/tratamiento farmacológico , Convulsiones/tratamiento farmacológico , Ácido gamma-Aminobutírico/análogos & derivados , Animales , Anticonvulsivantes/administración & dosificación , Anticonvulsivantes/efectos adversos , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Epilepsia/metabolismo , Femenino , Ataxia de la Marcha/tratamiento farmacológico , Ataxia de la Marcha/metabolismo , Excitación Neurológica , Masculino , Ratones , Ratones Endogámicos , Actividad Motora/efectos de los fármacos , Pregabalina , Ratas , Ratas Sprague-Dawley , Ratas Wistar , Convulsiones/inducido químicamente , Convulsiones/metabolismo , Ácido gamma-Aminobutírico/administración & dosificación , Ácido gamma-Aminobutírico/efectos adversos , Ácido gamma-Aminobutírico/farmacocinéticaRESUMEN
Pregabalin exhibits robust activity in preclinical assays indicative of potential antiepileptic, anxiolytic, and antihyperalgesic clinical efficacy. It binds with high affinity to the alpha(2)-delta subunit of voltage-gated calcium channels and is a substrate of the system L neutral amino acid transporter. A series of pregabalin analogues were prepared and evaluated for their alpha(2)-delta binding affinity as demonstrated by their ability to inhibit binding of [(3)H]gabapentin to pig brain membranes and for their potency to inhibit the uptake of [(3)H]leucine into CHO cells, a measure of their ability to compete with the endogenous substrate at the system L transporter. Compounds were also assessed in vivo for their ability to promote anxiolytic, analgesic, and anticonvulsant actions. These studies suggest that distinct structure activity relationships exist for alpha(2)-delta binding and system L transport inhibition. However, both interactions appear to play an important role in the in vivo profile of these compounds.
Asunto(s)
Sistema de Transporte de Aminoácidos L/metabolismo , Analgésicos/síntesis química , Ansiolíticos/síntesis química , Anticonvulsivantes/síntesis química , Canales de Calcio/metabolismo , Ácido gamma-Aminobutírico/análogos & derivados , Ácido gamma-Aminobutírico/síntesis química , Aminas/antagonistas & inhibidores , Aminas/metabolismo , Analgésicos/química , Analgésicos/farmacología , Animales , Ansiolíticos/química , Ansiolíticos/farmacología , Anticonvulsivantes/química , Anticonvulsivantes/farmacología , Encéfalo/metabolismo , Células CHO , Cricetinae , Cricetulus , Ácidos Ciclohexanocarboxílicos/antagonistas & inhibidores , Ácidos Ciclohexanocarboxílicos/metabolismo , Gabapentina , Técnicas In Vitro , Leucina/antagonistas & inhibidores , Leucina/metabolismo , Masculino , Ratones , Ratones Endogámicos DBA , Pregabalina , Unión Proteica , Subunidades de Proteína/metabolismo , Ratas , Relación Estructura-Actividad , Porcinos , Ácido gamma-Aminobutírico/química , Ácido gamma-Aminobutírico/metabolismo , Ácido gamma-Aminobutírico/farmacologíaRESUMEN
As part of a program aimed at generating compounds with affinity for the alpha(2)-delta subunit of voltage-gated calcium channels, several novel beta-amino acids were prepared using an efficient nitroalkane-mediated cyclopropanation as a key step. Depending on the ester that was chosen, the target amino acids could be prepared in as few as three steps. The cyclopropyl amino acids derived from ketones proved to be potent binders of the alpha(2)-delta subunit of voltage-gated calcium channels, but did not interact with the large neutral amino acid system L (leucine) transporter. Anticonvulsant effects were observed in vivo with compound 34 but only after intracerebroventricular (icv) administration, presumably due to inadequate brain concentrations of the drug being achieved following oral dosing. However, pregabalin 1 was active in the DBA/2 model after oral (and icv) dosing, supporting a hypothesis that active transport is a prerequisite for such zwitterionic species to cross the blood-brain barrier.