Asunto(s)
Transferasas Alquil y Aril/antagonistas & inhibidores , Transferasas Alquil y Aril/química , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Inhibidores Enzimáticos/química , Farnesiltransferasa , Espectroscopía de Resonancia Magnética , Conformación Molecular , Relación Estructura-ActividadRESUMEN
A series of aryloxy substituted piperazinones with dual farnesyltransferase/geranylgeranyltransferase-I inhibitory activity was prepared. These compounds were found to have potent inhibitory activity in vitro and are promising agents for the inhibition of Ki-Ras signaling.
Asunto(s)
Transferasas Alquil y Aril/antagonistas & inhibidores , Inhibidores Enzimáticos/farmacología , Piperazinas/farmacología , Diseño de Fármacos , Inhibidores Enzimáticos/química , Farnesiltransferasa , Genes ras/efectos de los fármacos , Piperazinas/química , Polímeros/química , Transducción de Señal/efectos de los fármacos , Relación Estructura-ActividadRESUMEN
The evaluation of SAR associated with the insertion of carbonyl groups at various positions of N-arylpiperazinone farnesyltransferase inhibitors is described herein. 1-Aryl-2,3-diketopiperazine derivatives exhibited the best balance of potency and pharmacokinetic profile relative to the parent 1-aryl-2-piperazinones.
Asunto(s)
Transferasas Alquil y Aril/antagonistas & inhibidores , Inhibidores Enzimáticos/farmacología , Piperazinas/farmacología , Animales , Perros , Inhibidores Enzimáticos/farmacocinética , Farnesiltransferasa , Relación Estructura-ActividadRESUMEN
A new synthesis of the 3,8-diazabicyclo[3.2.1]octan-2-one framework is described. Transannular enolate alkylation of piperazinone derivatives provides a flexible route to highly constrained bicyclic peptidomimetic synthons with substitution at the Calpha position. The chemistry was used to produce a conformationally constrained farnesyltransferase inhibitor, which aided the elucidation of enzyme-bound conformation.
Asunto(s)
Transferasas Alquil y Aril/antagonistas & inhibidores , Compuestos Bicíclicos Heterocíclicos con Puentes/síntesis química , Inhibidores Enzimáticos/síntesis química , Péptidos/química , Compuestos Bicíclicos Heterocíclicos con Puentes/química , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacología , Inhibidores Enzimáticos/química , Farnesiltransferasa , Indicadores y Reactivos , Modelos Moleculares , Conformación Molecular , Estructura Molecular , TermodinámicaAsunto(s)
Transferasas Alquil y Aril/antagonistas & inhibidores , Inhibidores Enzimáticos/síntesis química , Imidazoles/síntesis química , Piperazinas/síntesis química , Animales , Inhibidores Enzimáticos/farmacología , Farnesiltransferasa , Humanos , Imidazoles/farmacología , Ratones , Ratones Desnudos , Modelos Moleculares , Piperazinas/farmacología , Ratas , Células Tumorales CultivadasRESUMEN
The 4-oxospiro[benzopyran-2,4'-piperidine] ring system is contained within potent class III antiarrhythmic agents. We highlight how these agents can be chemically transformed into a new class of potent (< 1 nM) and selective (> 25-fold) alpha 1a-receptor subtype adrenergic antagonists.
Asunto(s)
Antagonistas de Receptores Adrenérgicos alfa 1 , Benzopiranos/farmacología , Piperidinas/farmacología , Compuestos de Espiro/farmacología , Animales , Antiarrítmicos/síntesis química , Humanos , Masculino , Hiperplasia Prostática/tratamiento farmacológico , RatasRESUMEN
Benign prostatic hyperplasia can be managed pharmacologically with alpha-1 adrenergic receptor antagonists. Agents that demonstrate selectivity for the alpha-1a receptor subtype may offer advantages in clinical applications with respect to hypotensive side effects. The N-alkylated saccharins reported here represent a new class of subtype selective alpha-1a adrenergic receptor antagonists which demonstrate potent effects on prostate function in vivo and are devoid of blood pressure side effects.
Asunto(s)
Antagonistas de Receptores Adrenérgicos alfa 1 , Antagonistas Adrenérgicos alfa/síntesis química , Diseño de Fármacos , Sacarina/análogos & derivados , Antagonistas Adrenérgicos alfa/farmacología , Alquilación , Animales , Aorta/efectos de los fármacos , Células CHO , Línea Celular , Cricetinae , Perros , Finasterida/química , Finasterida/farmacología , Humanos , Técnicas In Vitro , Masculino , Modelos Químicos , Prazosina/análogos & derivados , Prazosina/química , Prazosina/farmacología , Próstata/efectos de los fármacos , Ratas , Receptores Adrenérgicos alfa 1 , Sacarina/síntesis química , Sacarina/farmacología , Relación Estructura-Actividad , Sulfonamidas/química , Sulfonamidas/farmacología , TamsulosinaRESUMEN
A series of imidazobenzodiazepines, non-peptide antagonists of the peptide hormone cholecystokinin (CCK), are described. Derived by chemical modification of the benzodiazepine ring system embedded within the CCK-B antagonist L-365,260, these compounds display CCK-B/CCK-A selectivity and some analogs have receptor binding affinities in the subnanomolar range. This group of novel imidazobenzodiazepines, among which N-[(2S,4R)-methyl-6-phenyl-2,4-dihydro-1H-imidazo[1,2- alpha][1,4]benzodiazepin-4-yl]-N'-[3-methylphenyl]-urea (12) is the principal compound, expands the structural diversity of the collection of non-peptide CCK-B antagonists and will be useful in further delineating the function of CCK in the central nervous system.