Abstract
1-Arylnaphthalene lignan, which had been reported as a PDE4 inhibitor by Iwasaki, was disclosed as a new structural class of PDE5 inhibitors. The structural requirements for potent and specific PDE5 inhibition were revealed in a 1-arylnaphthalene lignan series, in which 1-(3-bromo-4, 5-dimethoxyphenyl)-5-chloro-3-[4-(2-hydroxyethyl)-1-piperazinylcarbon yl]-2-(methoxycarbonyl)naphthalene hydrochloride (27q) showed the most potent and specific inhibition (PDE5 inhibition IC50 = 6.2 nM, selectivity for PDE5 against PDE1, -2, -3, and -4 >16 000). It is noteworthy that 27q has the best selectivities against PDE isoforms among PDE5 inhibitors so far reported. Compound 27q exhibited almost the same relaxant effects on rat aortic rings as sodium 1-[6-chloro-4-[(3, 4-methylenedioxybenzyl)amino]quinazolin-2-yl]piperidine-4-ca rboxylate (35) (27q, EC50 = 0.10 microM; 35, EC50 = 0.20 microM) and was selected for further biological evaluation.
MeSH terms
-
3',5'-Cyclic-GMP Phosphodiesterases
-
Animals
-
Aorta / drug effects
-
Cardiovascular Agents / chemical synthesis*
-
Cardiovascular Agents / chemistry
-
Cardiovascular Agents / pharmacology
-
Coronary Vessels / drug effects
-
Cyclic Nucleotide Phosphodiesterases, Type 5
-
Dogs
-
Heart / drug effects
-
In Vitro Techniques
-
Isoenzymes / antagonists & inhibitors
-
Lignans / chemistry*
-
Muscle Contraction / drug effects
-
Muscle Relaxation / drug effects
-
Muscle, Smooth, Vascular / drug effects
-
Myocardium / enzymology
-
Naphthalenes / chemical synthesis*
-
Naphthalenes / chemistry
-
Naphthalenes / pharmacology
-
Phosphodiesterase Inhibitors / chemical synthesis*
-
Phosphodiesterase Inhibitors / chemistry
-
Phosphodiesterase Inhibitors / pharmacology
-
Phosphoric Diester Hydrolases / metabolism*
-
Piperazines / chemical synthesis*
-
Piperazines / chemistry
-
Piperazines / pharmacology
-
Rats
-
Structure-Activity Relationship
-
Swine
Substances
-
1-(3-bromo-4,5-dimethoxyphenyl)-5-chloro-3-(4-(2-hydroxyethyl)-1-piperazinylcarbonyl)-2-(methoxycarbonyl)naphthalene
-
Cardiovascular Agents
-
Isoenzymes
-
Lignans
-
Naphthalenes
-
Phosphodiesterase Inhibitors
-
Piperazines
-
Phosphoric Diester Hydrolases
-
3',5'-Cyclic-GMP Phosphodiesterases
-
Cyclic Nucleotide Phosphodiesterases, Type 5
-
Pde5a protein, rat