title: Cyclic GMP phosphodiesterase inhibitors. 1. The discovery of a novel potent inhibitor, 4-((3,4-(methylenedioxy)benzyl)amino)-6,7,8-trimethoxyquinazoline.
abstract: A newly synthesized compound, 4-((3,4-(methylenedioxy)benzyl)amino)-6,7,8-trimethoxyquinazoline (6), had a potent (IC50 = 0.36 microM) inhibitory action on cyclic GMP phosphodiesterase (cGMP-PDE) isolated from porcine aorta; its inhibitory activities toward other PDE isozymes were at least 10-fold weaker. In addition, 6 relaxed porcine coronary arteries precontracted with PGF2 alpha (EC50 = 1.96 +/- 0.58 microM). At the concentration of 30 microM, 6 caused elevation of the intracellular cGMP level in porcine coronary arteries without any change in cAMP level. Various other 4-substituted 6,7,8-trimethoxyquinazolines were also synthesized and evaluated for cGMP-PDE inhibitory activity. From their structure-activity relationships, we concluded that the 4-((3,4-(methylenedioxy)benzyl)-amino) group is essential for potent inhibition of cGMP-PDE.
authors.affiliation: Tsukuba Research Laboratories, Eisai Co. Ltd., Ibaraki, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Takase
authors.forename: T
authors.initials: T
authors.lastname: Saeki
authors.forename: M
authors.initials: M
authors.lastname: Fujimoto
authors.forename: I
authors.initials: I
authors.lastname: Saito
mesh_terms: D015106:3',5'-Cyclic-GMP Phosphodiesterases / Q000037:antagonists & inhibitors*; D000818:Animals; D001011:Aorta / Q000201:enzymology; D002867:Chromones / Q000737:chemistry / Q000494:pharmacology; D003331:Coronary Vessels / Q000187:drug effects / Q000502:physiology; D006152:Cyclic GMP / Q000378:metabolism; D015237:Dinoprost / Q000494:pharmacology; D007527:Isoenzymes / Q000037:antagonists & inhibitors; D015394:Molecular Structure; D009126:Muscle Relaxation / Q000187:drug effects; D011688:Purinones / Q000494:pharmacology; D011799:Quinazolines / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013552:Swine
chemical_list: D002867:Chromones; D007527:Isoenzymes; D011688:Purinones; D011799:Quinazolines; C084663:4-((3,4-(methylenedioxy)benzyl)amino)-6,7,8-trimethoxyquinazoline; C006312:FPL 55712; D015237:Dinoprost; D015106:3',5'-Cyclic-GMP Phosphodiesterases; C011145:zaprinast; D006152:Cyclic GMP