RESUMEN
Novel arylpiperazines were identified as alpha 1-adrenoceptor (AR) subtype-selective antagonists by functional in vitro screening. 3-[4-(ortho-Substituted phenyl)piperazin-1-yl]propylamines were derivatized with N,N-dimethyl anthranilamides, nicotinamides, as well as carboxamides of quinoline, 1,8-naphthyridine, pyrazolo[3,4-b]pyridine, isoxazolo[3,4-b]pyridine, imidazo[4,5-b]pyridine, and pyrazolo[1,5-a]pyrimidines. Strips of rabbit bladder neck were employed as a predictive assay for antagonism in the human lower tract. Rings of rat aorta were used as a "negative screen" for the test antagonists. Binding to alpha 1-ARs was relatively sensitive to size and electronic features of the arylpiperazine portion of the antagonists and permissive to these features on the heteroaryl carboxamide side. These structure-affinity findings were exploited to produce nicotinamides (e.g. 13ii and 25x) and pyrazolo[3,4-b]pyridines (e.g. 37f and 37y) ligands with nanomolar affinity at the alpha 1-AR subtype prevalent in the human lower urinary tract(pA2 values: 8.8, 10.7, 9.3, and 9.9, respectively) and displaying 2-3 orders of magnitude selectivity over the alpha 1D-AR.
Asunto(s)
Antagonistas de Receptores Adrenérgicos alfa 1 , Antagonistas Adrenérgicos alfa/síntesis química , Amidas/síntesis química , Piperazinas/síntesis química , Propilaminas/síntesis química , Vejiga Urinaria/efectos de los fármacos , Adolescente , Antagonistas Adrenérgicos alfa/farmacología , Antagonistas Adrenérgicos alfa/uso terapéutico , Adulto , Anciano , Amidas/farmacología , Amidas/uso terapéutico , Animales , Unión Competitiva , Humanos , Masculino , Persona de Mediana Edad , Modelos Químicos , Músculo Liso/efectos de los fármacos , Músculo Liso/metabolismo , Piperazinas/farmacología , Piperazinas/uso terapéutico , Prazosina/metabolismo , Propilaminas/farmacología , Propilaminas/uso terapéutico , Hiperplasia Prostática/tratamiento farmacológico , Conejos , Ratas , Relación Estructura-Actividad , Vejiga Urinaria/metabolismoRESUMEN
Structure-activity relationships in the region of the phthalide ring of the inosine monophosphate dehydrogenase inhibitor mycophenolic acid have been explored. Replacement of the lactone ring with other cyclic moieties resulted in loss of potency, especially for larger groups. Replacement of the ring by acyclic substituents also indicated a strong sensitivity to steric bulk. A phenolic hydroxyl group, with an adjacent hydrogen bond acceptor, was found to be essential for high potency. The aromatic methyl group was essential for activity; the methoxyl group could be replaced by ethyl to give a compound with 2-4 times the potency of mycophenolic acid in vitro and in vivo.
Asunto(s)
IMP Deshidrogenasa/antagonistas & inhibidores , Ácido Micofenólico/análogos & derivados , Animales , División Celular/efectos de los fármacos , Femenino , Técnica de Placa Hemolítica , Humanos , Linfocitos/citología , Linfocitos/efectos de los fármacos , Ratones , Ratones Endogámicos C3H , Ácido Micofenólico/farmacología , Proteínas Recombinantes/antagonistas & inhibidores , Relación Estructura-ActividadRESUMEN
A series of alpha-cyano-beta-hydroxypropenamides was prepared and tested for anthelmintic activity. alpha-Cyano-beta-hydroxy-N-[4- (trifluoromethyl)phenyl]-3-[4-(trifluoromethyl)phenyl]propenamide (1) showed good activity against the nematode Nematospirodes dubius in a mixed parasite infection in mice; several of the analogues were also effective against the cestode Hymenolepis nana. In sheep trials, 1 caused 100% reduction of the hematophagous nematode Haemonchus contortus after a single dose of 20 mg/kg but did not show satisfactory control of Trichostrongylus colubriformis or Ostertagia circumcincta. Against the liver fluke Fasciola hepatica, 1 suppressed egg production but only temporarily, suggesting that the adult flukes were not eliminated. Mechanism of action studies on 1 using Ascaris mitochondria showed it to be an uncoupler of oxidative phosphorylation.
Asunto(s)
Amidas/síntesis química , Antihelmínticos/síntesis química , Nitrilos/síntesis química , Amidas/uso terapéutico , Animales , Antihelmínticos/uso terapéutico , Femenino , Masculino , Ratones , Infecciones por Nematodos/tratamiento farmacológico , Nitrilos/uso terapéutico , Ovinos , Relación Estructura-ActividadRESUMEN
Screening of mesoionic compounds as potential electron acceptors by analogy with metronidazole led to the finding of in vitro antitrichomonal activity for anhydro-2-phenyl-3-hydroxythiazolo [3,2-a]pyridinium hydroxide (1). In a series of analogues, potent in vitro activity was found to be associated with amino substitution; however, such activity was dependent on specific structural features and not on the reduction potential. The most active compounds showed only poor in vivo activity.