1-Arylnaphthalene lignan: a novel scaffold for type 5 phosphodiesterase inhibitor.
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.
Ukita
T
T
Discovery Research Laboratory, Tanabe Seiyaku Company, Ltd., 3-16-89, Kashima, Yodogawa, Osaka 532-8505, Japan.
Nakamura
Y
Y
Kubo
A
A
Yamamoto
Y
Y
Takahashi
M
M
Kotera
J
J
Ikeo
T
T
D015106:3',5'-Cyclic-GMP Phosphodiesterases; D000818:Animals; D001011:Aorta / Q000187:drug effects; D002317:Cardiovascular Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D003331:Coronary Vessels / Q000187:drug effects; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; D004285:Dogs; D006321:Heart / Q000187:drug effects; D066298:In Vitro Techniques; D007527:Isoenzymes / Q000037:antagonists & inhibitors; D017705:Lignans / Q000737:chemistry*; D009119:Muscle Contraction / Q000187:drug effects; D009126:Muscle Relaxation / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D009206:Myocardium / Q000201:enzymology; D009281:Naphthalenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010726:Phosphodiesterase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism*; D010879:Piperazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D013329:Structure-Activity Relationship; D013552:Swine
C118880:1-(3-bromo-4,5-dimethoxyphenyl)-5-chloro-3-(4-(2-hydroxyethyl)-1-piperazinylcarbonyl)-2-(methoxycarbonyl)naphthalene; D002317:Cardiovascular Agents; D007527:Isoenzymes; D017705:Lignans; D009281:Naphthalenes; D010726:Phosphodiesterase Inhibitors; D010879:Piperazines; D010727:Phosphoric Diester Hydrolases; D015106:3',5'-Cyclic-GMP Phosphodiesterases; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; C517384:Pde5a protein, rat