RESUMEN
Following the disclosure of 3-(1,2,2-trimethylpropyl) 4-[3,5-dimethyl-2-propyloxycarbonyl]pyrrolecarboxylate as a potent and selective mGluR1 non-competitive antagonist, the role and the importance of the pyrrole template were investigated. Different aromatic moieties were investigated as possible bio-isosteric replacement of the original scaffold and some of them were shown to be partially able to mimic the properties of the original pyrrole ring.
Asunto(s)
Analgésicos no Narcóticos/síntesis química , Pirroles/síntesis química , Receptores de Glutamato Metabotrópico/antagonistas & inhibidores , Analgésicos no Narcóticos/farmacología , Animales , Derivados del Benceno/química , Derivados del Benceno/farmacología , Unión Competitiva/efectos de los fármacos , Células CHO , Cricetinae , Ésteres/síntesis química , Ésteres/farmacología , Concentración 50 Inhibidora , Ratones , Nociceptores/efectos de los fármacos , Dimensión del Dolor , Pirroles/farmacología , Ratas , Receptores de Glutamato Metabotrópico/química , Receptores de Glutamato Metabotrópico/genética , Médula Espinal/efectos de los fármacos , Médula Espinal/metabolismo , Relación Estructura-Actividad , Tiofenos/química , Tiofenos/farmacologíaRESUMEN
Following the recent disclosure of 3-methyl pyrrole-2,4-dicarboxylic acid 2-propyl ester 4-(1,2,2-trimethyl-propyl) ester, a potent and selective mGluR1 non-competitive antagonist, we report here a detailed exploration of the C-2 position of this scaffold with the preparation of differently substituted amides. Great improvement of the pharmacokinetic properties has been achieved through this exercise.
Asunto(s)
Ésteres/síntesis química , Ésteres/farmacología , Pirroles/síntesis química , Pirroles/farmacología , Receptores de Glutamato Metabotrópico/antagonistas & inhibidores , Amidas/síntesis química , Amidas/farmacocinética , Animales , Azidas/síntesis química , Azidas/farmacocinética , Fenómenos Químicos , Química Física , Cromatografía Líquida de Alta Presión , Cromatografía en Capa Delgada , Ácidos Hidroxámicos/síntesis química , Ácidos Hidroxámicos/farmacocinética , Indicadores y Reactivos , Espectroscopía de Resonancia Magnética , Espectrometría de Masas , Ratones , Conformación Molecular , Ratas , Solubilidad , Espectrofotometría Infrarroja , Relación Estructura-ActividadRESUMEN
Exploiting the SAR of the known pyrrole derivatives, a new class of mGluR1 antagonists was designed by replacement of the pyrrole core with an indole scaffold and consequent cyclization of the C-2 position into a tricyclic beta-carboline template. The appropriate exploration of the position C-6 with a combination of H-bond acceptor groups coupled with bulky/lipophilic moieties led to the discovery of a new series of mGluR1 antagonists. These compounds exhibited a non-competitive behavior, excellent pharmacokinetic properties, and good in vivo activity in animal models of acute and chronic pain, after oral administration.
Asunto(s)
Carbolinas/síntesis química , Carbolinas/farmacocinética , Antagonistas de Aminoácidos Excitadores/síntesis química , Dolor/tratamiento farmacológico , Receptores de Glutamato Metabotrópico/antagonistas & inhibidores , Administración Oral , Analgésicos/síntesis química , Analgésicos/farmacología , Animales , Carbolinas/uso terapéutico , Modelos Animales de Enfermedad , Diseño de Fármacos , Antagonistas de Aminoácidos Excitadores/farmacocinética , Antagonistas de Aminoácidos Excitadores/uso terapéutico , Humanos , Concentración 50 Inhibidora , Ligandos , Ratones , Relación Estructura-ActividadRESUMEN
Exploiting the SAR of the known pyrrole derivatives, a new class of mGluR1 antagonists was developed through a cyclization of the C-2 position on the pyrrole N-1 nitrogen. The resulting pyrrolo[1,2-a]pyrazinones are potent and noncompetitive antagonists.
Asunto(s)
Pirazinas/química , Pirazinas/farmacología , Pirroles/química , Receptores de Glutamato Metabotrópico/antagonistas & inhibidores , Animales , Células CHO , Cricetinae , Concentración 50 Inhibidora , Estructura Molecular , Receptores de Glutamato Metabotrópico/metabolismo , Relación Estructura-ActividadRESUMEN
Following the disclosure of 3,5-dimethyl pyrrole-2,4-dicarboxylic acid 2-propyl ester 4-(1,2,2-trimethyl-propyl) ester [3,5-dimethyl PPP] as a potent and selective mGluR1 non-competitive antagonist, we report here further in vivo characterization of this important tool and disclose the investigation of the C-5 position, which led to very potent compounds.
Asunto(s)
Ésteres/síntesis química , Antagonistas de Aminoácidos Excitadores/síntesis química , Antagonistas de Aminoácidos Excitadores/farmacología , Pirroles/síntesis química , Receptores de Glutamato Metabotrópico/antagonistas & inhibidores , Animales , Unión Competitiva/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Electrofisiología , Ésteres/farmacología , Indicadores y Reactivos , Morfina/farmacología , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Nociceptores/efectos de los fármacos , Pirroles/farmacología , Ratas , Médula Espinal/efectos de los fármacos , Médula Espinal/metabolismo , Relación Estructura-Actividad , Transmisión Sináptica/efectos de los fármacos , Tálamo/efectos de los fármacos , Tálamo/metabolismoRESUMEN
Metabotropic glutamate receptors (mGluRs) are an unusual family of G-protein coupled receptor (GPCR), and are characterised by a large extracellular N-terminal domain that contains the glutamate binding site. We have identified a new class of non-competitive metabotropic glutamate receptor 1 (mGluR1) antagonists, 2,4-dicarboxy-pyrroles which are endowed with nanomolar potency. They interact within the 7 transmembrane (7TM) domain of the receptor and show antinociceptive properties when tested in a number of different animal models.