DISCOVERY OF POTENT CYCLIC-GMP PHOSPHODIESTERASE INHIBITORS - 2-PYRIDYLQUINAZOLINES AND 2-IMIEDAZOLYLQUINAZOLINES POSSESSING CYCLIC-GMP PHOSPHODIESTERASE AND THROMBOXANE SYNTHESIS INHIBITORY ACTIVITIES

Moderate cyclic GMP phosphodiesterase (cGMP-PDE, PDE V) inhibitor 2-ph enyl-4-anilino-quinazoline (1) was identified utilizing MultiCASE assi sted drug design (MCADD) technology. Modification of compound 1 was co nducted at the 2-, 4-, and 6-positions of the quinazoline ring for enh ancement of cGMP-PDE inhibitory activity. The 6-substituted 2-(imidazo l-1-yl)-quinazolines are 1000 times more potent in in vitro PDE V enzy me assay than the well-known inhibitor zaprinast. The 6-substituted de rivatives of 2-(3-pyridyl)quinazoline 84 and 2-(imidazol-1-yl)quinazol ine 86 exhibited more than 1000-fold selectivity for PDE V over the ot her four PDE isozymes. In addition, cGMP-PDE inhibitors 64, 65, and 73 were found to have an additional property of thromboxane synthesis in hibitory activity.