RESUMEN
Novel 1,7- and 2,7-naphthyridine derivatives, designed by the introduction of nitrogen atom into the phenyl ring of previously reported 4-aryl-1-isoquinolinone derivatives, were disclosed as a new structural class of potent and specific PDE5 inhibitors. Among them, 2,7-naphthyridine 4c showed potent PDE5 inhibition (IC(50)=0.23 nM) and one of the best PDE5 specificities against PDEs1-4,6 (>100,000-fold selective versus PDE1-4, 240-fold selective vs PDE6). This compound showed more potent relaxant effects on isolated rabbit corpus cavernosum (EC(30)=5.0 nM) than Sildenafil (EC(30)=8.7 nM). The compound 4c (T-0156) was selected for further biological and pharmacological evaluation of erectile dysfunction.
Asunto(s)
Naftiridinas/síntesis química , Naftiridinas/farmacología , Inhibidores de Fosfodiesterasa/síntesis química , Inhibidores de Fosfodiesterasa/farmacología , Hidrolasas Diéster Fosfóricas/efectos de los fármacos , 3',5'-GMP Cíclico Fosfodiesterasas , Animales , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 5 , Genitales Masculinos/efectos de los fármacos , Técnicas In Vitro , Indicadores y Reactivos , Isoenzimas/antagonistas & inhibidores , Masculino , Relajación Muscular/efectos de los fármacos , Músculo Liso/efectos de los fármacos , Piperazinas/farmacología , Purinas , Conejos , Citrato de Sildenafil , Relación Estructura-Actividad , SulfonasRESUMEN
A novel series of 1-pyridylisoquinoline and 1-pyridyldihydroisoquinoline derivatives has been prepared. These compounds showed potent PDE4 inhibitory activities and a broad margin between the K(i) value of the rolipram binding affinity and the IC(50) value of PDE4 inhibition. They also exhibited potent inhibitory activities toward LPS-induced TNF-alpha production in mice.
Asunto(s)
3',5'-AMP Cíclico Fosfodiesterasas/antagonistas & inhibidores , Inhibidores de Fosfodiesterasa/síntesis química , Inhibidores de Fosfodiesterasa/farmacología , Animales , Unión Competitiva/efectos de los fármacos , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 4 , Relación Dosis-Respuesta a Droga , Indicadores y Reactivos , Isoquinolinas/síntesis química , Cinética , Lipopolisacáridos/antagonistas & inhibidores , Lipopolisacáridos/farmacología , Ratones , Inhibidores de Fosfodiesterasa/metabolismo , Quinolinas/síntesis química , Rolipram/metabolismo , Estereoisomerismo , Factor de Necrosis Tumoral alfa/biosíntesisRESUMEN
[reaction: see text] alpha-Diazophosphonates, which have extremely useful properties from a synthetic point of view, are disclosed as 1,1-ambiphilic one-carbon building blocks for one-pot construction of various heterocyclic compounds. They are easily prepared and have higher stability by the effect of the phosphoryl group than corresponding alpha-diazocarbonyl compounds. Using this synthon, we have developed a novel, mild, and efficient synthetic method of 2,3-disubstituted indoles and 3,4-disubstituted isocoumarins.
Asunto(s)
Cumarinas/síntesis química , Compuestos de Diazonio/síntesis química , Compuestos Heterocíclicos/síntesis química , Indoles/síntesis química , Compuestos Organofosforados/síntesis química , Catálisis , Cumarinas/química , Compuestos de Diazonio/química , Compuestos Heterocíclicos/química , Indicadores y Reactivos , Indoles/química , Compuestos Organofosforados/químicaRESUMEN
Cis- and trans-isomers of alpha-hydroxy-alpha,beta-dibenzyl-gamma-butyrolactone lignans 1a,d-g and 2a,c,d were stereoselectively synthesized in good yields based on the electrophilic addition to the metal enolate of alpha-benzyl-gamma-butyrolactone derivatives 1l-o and 3 as a key step. This method was applied to the syntheses of (+/-)-trachelogenin and (+/-)-guayadequiol, representative examples of the trans- and cis-isomers of alpha-hydroxy-alpha,beta-dibenzyl-gamma-butyrolactone lignan series.