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.
SummaryTwo kinds of high-speed liquid chromatographic methods using either ultraviolet or a fluorometric detector (HSLC-UV and HSLC fluorometric methods) are described for the determination of ubiquinones (UQ). HSLC-UV method: Serum or liver was saponified with methanolic alkaline solution containing pyrogallol as an antioxidant and 2, 3, 6 trimethyl-5-nonaprenyl-l, 4-benzoquinone as an internal standard and then extracted with n-hexane. The extract was evaporated and then dissolved in dioxane. The resulting solution was applied to a HSLC system using a Permaphase ODS column, ethanol-water (80:20) as a mobile phase and a high sensitivity UV detector (275nm). HSLC-fluorometric metho: Serum was deproteinized with ethanol and then extracted with n-hexane. The resulting extract was reacted with alkaline ethylcyanoacetate (ECA) reagent to give fluorescence. The reacted solution was applied to a HSLC system using a Permaphase ODS column, ethanol-water (75: 25) as a mobile phase and a spectrofluorometer (Ex. 430nm, Em. 530nm). Neither of the proposed HSLC methods were affected by other fat-soluble substances and seemed to be more simple, sensitive and specific than other conventional determination methods.It is well known that ubiquinones (UQ) play an important role in the mitochondrial electron transport chain of respiration . These compounds are also used for the therapy of human diseases. In order to investigate the role of UQ in animals and human beings, it is necessary to establish a simple and precise method for the determination of these compounds in biological materials .
Structure-activity relationships of antimutagens were studied by assaying analogues and derivatives of 2(5//)furanone designed on the basis of the structures of natual antimutagens by the method of observing UV-induced reversion ofE. coli WP2B/r uvr A~trp E~. It is shown that an a,/?-unsaturated carbonyl system is required for antimutagenic activity. Further modification of 3(2i/)furanones resulted in the development of a highly potent antimutagen. The possibility that the antimutagenic effects maybe due to alteration of proteins involved in the DNArepair system by trapping thiol groups is also discussed.
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