RESUMO
8-Chlorodibenz[b,f][1,4]oxazepine-10(11H)-carboxylic acid, 2-[1-oxo-3-(4-pyridinyl)propyl]hydrazide, monohydrochloride (1, SC-51089) is a functional PGE2 antagonist selective for the EP1 receptor subtype with antinociceptive activity. Analogues of SC-51089, in which the diacylhydrazine moiety has been replaced with 2,4-disubstituted-oxazoles and-thiazoles, are described.
Assuntos
Dinoprostona/antagonistas & inibidores , Hidrazinas/química , Oxazepinas/química , Oxazóis/síntese química , Tiazóis/síntese químicaAssuntos
Inibidores Enzimáticos/uso terapêutico , Óxido Nítrico Sintase/antagonistas & inibidores , Sepse/tratamento farmacológico , Animais , Linhagem Celular , Modelos Animais de Doenças , Humanos , Lipopolissacarídeos/toxicidade , Camundongos , Óxido Nítrico Sintase Tipo II , Nitritos/urina , Fator de Necrose Tumoral alfa/análiseRESUMO
A series of substituted 2-iminopyrrolidines has been prepared and shown to be potent and selective inhibitors of the human inducible nitric oxide synthase (hiNOS) isoform versus the human endothelial nitric oxide synthase (heNOS) and the human neuronal nitric oxide synthase (hnNOS). Simple substitutions at the 3-, 4-, or 5-position afforded more potent analogues than the parent 2-iminopyrrolidine 1. The effect of ring substitutions on both potency and selectivity for the different NOS isoforms is described. Substitution at the 4- and 5-positions of the 2-iminopyrrolidine yielded both potent and selective inhibitors of hiNOS. In particular, (+)-cis-4-methyl-5-pentylpyrrolidin-2-imine, monohydrochloride (20), displayed potent inhibition of hiNOS (IC50 = 0.25 microM) and selectivities of 897 (heNOS IC50/hiNOS IC50) and 13 (hnNOS IC50/hiNOS IC50). Example 20 was shown to be an efficacious inhibitor of NO production in the mouse endotoxin assay. Furthermore, 20 displayed in vivo selectivity, versus heNOS isoform, by not elevating blood pressure at multiples of the effective dose in the mouse.
Assuntos
Inibidores Enzimáticos/síntese química , Iminas/síntese química , Isoenzimas/antagonistas & inibidores , Óxido Nítrico Sintase/antagonistas & inibidores , Pirrolidinas/síntese química , Animais , Pressão Sanguínea/efeitos dos fármacos , Indução Enzimática , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Humanos , Iminas/química , Iminas/farmacologia , Lipopolissacarídeos/farmacologia , Espectroscopia de Ressonância Magnética , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Neurônios/efeitos dos fármacos , Neurônios/enzimologia , Óxido Nítrico/antagonistas & inibidores , Óxido Nítrico Sintase Tipo II , Óxido Nítrico Sintase Tipo III , Pirrolidinas/química , Pirrolidinas/farmacologia , Estereoisomerismo , Relação Estrutura-AtividadeAssuntos
Inibidores Enzimáticos/síntese química , Álcoois Graxos/síntese química , Iminas/síntese química , Óxido Nítrico Sintase/antagonistas & inibidores , Indução Enzimática/efeitos dos fármacos , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Álcoois Graxos/química , Álcoois Graxos/farmacologia , Humanos , Iminas/química , Iminas/farmacologia , Espectroscopia de Ressonância Magnética , Óxido Nítrico Sintase/biossíntese , Óxido Nítrico Sintase Tipo II , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
8-Chlorodibenz[b,f][1,4]oxazepine-10(11H)-carboxylic acid, 2-[1-oxo-3-(4-pyridinyl)propyl]hydrazide, monohydrochloride (1, SC-51089) is a functional PGE2 antagonist selective for the EP1 receptor subtype with antinociceptive activity. During metabolism in cultured rat hepatocytes, SC-51089, which contains a diacylhydrazine moiety, has been shown to release hydrazine. Analogs of SC-51089, in which the diacylhydrazine functionality has been replaced by isosteric and isoelectronic groups, have been synthesized and have been shown to be analgesics and PGE2 antagonists of the EP1 subtype. This report discusses the structure-activity relationships within these series.
Assuntos
Analgésicos/farmacologia , Dinoprostona/antagonistas & inibidores , Hidrazinas/química , Hidrazinas/farmacologia , Oxazepinas/farmacologia , Antagonistas de Prostaglandina/farmacologia , Analgésicos/química , Animais , Células Cultivadas , Cobaias , Íleo/efeitos dos fármacos , Íleo/metabolismo , Técnicas In Vitro , Fígado/citologia , Fígado/efeitos dos fármacos , Espectroscopia de Ressonância Magnética , Oxazepinas/química , Antagonistas de Prostaglandina/química , RatosRESUMO
8-Chlorodibenz[b,f][1,4]oxazepine-10(11H)-carboxylic acid, 2-acetylhydrazide (1, SC-19220) has been previously reported by us and others to be a PGE2 antagonist selective for the EP1 receptor subtype with antinociceptive activities. Analogs of SC-19220, in which the acetyl moiety has been replaced with pyridylpropionyl groups and their homologs, have been synthesized as illustrated by compounds 13 and 29. These and other members of this series have been shown to be efficacious analgesics and PGE2 antagonists of the EP1 subtype. This report discusses the structure activity relationships within this series.
Assuntos
Analgésicos/síntese química , Analgésicos/farmacologia , Ácido Dibenzo(b,f)(1,4)oxazepina-10(11H)-carboxílico, 8-cloro-, 2-acetilidrazida/análogos & derivados , Dibenzoxazepinas/síntese química , Dibenzoxazepinas/farmacologia , Dinoprostona/antagonistas & inibidores , Animais , Fenômenos Químicos , Físico-Química , Cobaias , Técnicas In Vitro , Masculino , Camundongos , Camundongos Endogâmicos , Nociceptores/efeitos dos fármacos , Solubilidade , Relação Estrutura-Atividade , ÁguaRESUMO
Analogues of bradykinin were synthesized containing single substitutions by N alpha-methyl amino acids in the 1, 4, 5, 5, and 9 positions. [MeArg]Bradykinin possessed 60% of the muscle-contracting activity of the parent compound in a guinea pig ileum assay. The other analogues were very weak agonists (less than 2%) and, disappointingly, failed to show blocking activity except at very high doses.