RESUMO
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.
Assuntos
Naftiridinas/síntese química , Naftiridinas/farmacologia , Inibidores de Fosfodiesterase/síntese química , Inibidores de Fosfodiesterase/farmacologia , Diester Fosfórico Hidrolases/efeitos dos fármacos , 3',5'-GMP Cíclico Fosfodiesterases , Animais , Nucleotídeo Cíclico Fosfodiesterase do Tipo 5 , Genitália Masculina/efeitos dos fármacos , Técnicas In Vitro , Indicadores e Reagentes , Isoenzimas/antagonistas & inibidores , Masculino , Relaxamento Muscular/efeitos dos fármacos , Músculo Liso/efeitos dos fármacos , Piperazinas/farmacologia , Purinas , Coelhos , Citrato de Sildenafila , Relação Estrutura-Atividade , SulfonasRESUMO
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.
Assuntos
3',5'-AMP Cíclico Fosfodiesterases/antagonistas & inibidores , Inibidores de Fosfodiesterase/síntese química , Inibidores de Fosfodiesterase/farmacologia , Animais , Ligação Competitiva/efeitos dos fármacos , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4 , Relação Dose-Resposta a Droga , Indicadores e Reagentes , Isoquinolinas/síntese química , Cinética , Lipopolissacarídeos/antagonistas & inibidores , Lipopolissacarídeos/farmacologia , Camundongos , Inibidores de Fosfodiesterase/metabolismo , Quinolinas/síntese química , Rolipram/metabolismo , Estereoisomerismo , Fator de Necrose Tumoral alfa/biossínteseRESUMO
[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.
Assuntos
Cumarínicos/síntese química , Compostos de Diazônio/síntese química , Compostos Heterocíclicos/síntese química , Indóis/síntese química , Compostos Organofosforados/síntese química , Catálise , Cumarínicos/química , Compostos de Diazônio/química , Compostos Heterocíclicos/química , Indicadores e Reagentes , Indóis/química , Compostos Organofosforados/químicaRESUMO
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.
