CYCLIC-GMP PHOSPHODIESTERASE INHIBITORS .1. THE DISCOVERY OF A NOVEL POTENT INHIBITOR, 4-((3,4-(METHYLENEDIOXY)BENZYL)AMINO)-6,7,8-TRIMETHOXYQUINAZOLINE

A newly synthesized compound, 4-((3,4-(methylenedioxy)benzyl)amino)-6,7,8-trimethoxyquinazo-line (6), had a potent (IC50 = 0.36 mu M) 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 PGF(2 alpha), (EC(50) = 1.96 +/- 0.58 mu M). At the concentration of 30 mu M, 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.