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.
MeSH terms
-
3',5'-Cyclic-GMP Phosphodiesterases
-
Animals
-
Antihypertensive Agents / chemical synthesis*
-
Antihypertensive Agents / chemistry
-
Antihypertensive Agents / pharmacokinetics
-
Antihypertensive Agents / pharmacology
-
Biological Availability
-
Blood Pressure / drug effects
-
Coronary Vessels / drug effects
-
Coronary Vessels / physiology
-
Cyclic Nucleotide Phosphodiesterases, Type 5
-
Dinoprost / pharmacology
-
Hypertension, Pulmonary / drug therapy
-
Hypertension, Pulmonary / physiopathology
-
In Vitro Techniques
-
Male
-
Muscle Relaxation / drug effects
-
Muscle, Smooth, Vascular / drug effects
-
Muscle, Smooth, Vascular / physiology
-
Phosphodiesterase Inhibitors / chemical synthesis*
-
Phosphodiesterase Inhibitors / chemistry
-
Phosphodiesterase Inhibitors / pharmacokinetics
-
Phosphodiesterase Inhibitors / pharmacology
-
Phosphoric Diester Hydrolases / metabolism*
-
Phthalazines / chemical synthesis*
-
Phthalazines / chemistry
-
Phthalazines / pharmacokinetics
-
Phthalazines / pharmacology
-
Piperidines / chemical synthesis*
-
Piperidines / chemistry
-
Piperidines / pharmacokinetics
-
Piperidines / pharmacology
-
Quinazolines / pharmacology
-
Rats
-
Rats, Sprague-Dawley
-
Structure-Activity Relationship
-
Swine
-
Vasodilator Agents / chemical synthesis*
-
Vasodilator Agents / chemistry
-
Vasodilator Agents / pharmacokinetics
-
Vasodilator Agents / pharmacology
Substances
-
(4-(3-chloro-4-methoxybenzyl)amino-1-(4-hydroxy)piperidino)-6-phthalazinecarbonitrile
-
Antihypertensive Agents
-
E 4021
-
Phosphodiesterase Inhibitors
-
Phthalazines
-
Piperidines
-
Quinazolines
-
Vasodilator Agents
-
Dinoprost
-
Phosphoric Diester Hydrolases
-
3',5'-Cyclic-GMP Phosphodiesterases
-
Cyclic Nucleotide Phosphodiesterases, Type 5
-
Pde5a protein, rat