4-(3-Chloro-4-methoxybenzyl)aminophthalazines: synthesis and inhibitory activity toward phosphodiesterase 5.
J Med Chem
; 43(13): 2523-9, 2000 Jun 29.
Article
em En
| MEDLINE
| ID: mdl-10891111
ABSTRACT
We synthesized various 4-(3-chloro-4-methoxybenzyl)aminophthalazines substituted at the 1- and 6-positions and evaluated their inhibitory activity toward phosphodiesterase 5 (PDE5) and their vasorelaxant activity in isolated porcine coronary arteries precontracted with prostaglandin F2alpha (10(-5) M). The preferred substituents at the 1-position of the phthalazine were 4-hydroxypiperidino, 4-hydroxymethylpiperidino, 4-(2-hydroxyethyl)piperidino, and 4-oxopiperidino. Among these compounds, [4-(3-chloro-4-methoxybenzyl)amino-1-(4-hydroxy)piperidino]-6-phthala zinecarbonitrile monohydrochloride (13) exhibited potent PDE5 inhibitory activity (IC(50) = 0.56 nM) with >1700-fold high selectivity over other PDE isozymes (PDE1-4). Compound 13 exhibited the most potent vasorelaxant action (EC(50) = 13 nM) in this series of compounds. Compound 13 reduced mean pulmonary arterial pressure by 29.9 +/- 3.1% when administered intravenously at 30 microg/kg to the chronically hypoxic rats and had an apparent oral bioavailability of about 19.5% in rats and was selected for further biological evaluation.
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Base de dados:
MEDLINE
Assunto principal:
Inibidores de Fosfodiesterase
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Ftalazinas
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Piperidinas
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Vasodilatadores
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Diester Fosfórico Hidrolases
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Anti-Hipertensivos
Idioma:
En
Ano de publicação:
2000
Tipo de documento:
Article