RESUMO
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.
Assuntos
Antagonistas de Receptores Adrenérgicos alfa 1 , Antagonistas Adrenérgicos alfa/síntese química , Amidas/síntese química , Piperazinas/síntese química , Propilaminas/síntese química , Bexiga Urinária/efeitos dos fármacos , Adolescente , Antagonistas Adrenérgicos alfa/farmacologia , Antagonistas Adrenérgicos alfa/uso terapêutico , Adulto , Idoso , Amidas/farmacologia , Amidas/uso terapêutico , Animais , Ligação Competitiva , Humanos , Masculino , Pessoa de Meia-Idade , Modelos Químicos , Músculo Liso/efeitos dos fármacos , Músculo Liso/metabolismo , Piperazinas/farmacologia , Piperazinas/uso terapêutico , Prazosina/metabolismo , Propilaminas/farmacologia , Propilaminas/uso terapêutico , Hiperplasia Prostática/tratamento farmacológico , Coelhos , Ratos , Relação Estrutura-Atividade , Bexiga Urinária/metabolismoRESUMO
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.
