4-(3-Chloro-4-methoxybenzyl)aminophthalazines:  Synthesis and Inhibitory Activity toward Phosphodiesterase 5

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.

Investigations on Inhibitors of Hedgehog Signal Pathway: A Quantitative Structure-Activity Relationship Study

“…In binary Bayesian inference for each compound, the following steps were applied to predict their probability of being active [46]: Estimates two distributions: one for the active compounds and one for the inactive ones in the training set. The separation of active and inactive sets is manually defined by a Binary Threshold.…”

Amino- and polyaminophthalazin-1(2H)-ones: synthesis, coordination properties, and biological activity

“…Aminophthalazines have been also evaluated for their inhibitory activity toward phosphodiesterases such as PDE-5 ( Figure 1) [13,14] and PDE-10 [15] for a potential use in the treatment of chronic pain and neurodegenerative or psychiatric disorders. Some of these derivatives are known to possess anti-inflammatory (p38 MAP kinase inhibitors, Figure 1) [16], cardiotonic [17], and anticancer (Aurora-A kinase inhibitors) properties [18][19][20].…”

Synthesis and characterization of new phthalhydrazothiazole derivatives: A preliminary investigation on their activity against hepatocellular carcinoma

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