Moderate cyclic GMP phosphodiesterase (cGMP-PDE, PDE V) inhibitor 2-phenyl-4-anilino-quinazoline (1) was identified utilizing MultiCASE assisted drug design (MCADD) technology. Modification of compound 1 was conducted at the 2-, 4-, and 6-positions of the quinazoline ring for enhancement of cGMP-PDE inhibitory activity. The 6-substituted 2-(imidazol-1-yl)-quinazolines are 1000 times more potent in in vitro PDE V enzyme than the well-known inhibitor zaprinast. The 6-substituted derivatives of 2-(3-pyridyl)quinazoline 84 and 2-(imidazol-1-yl)quinazoline 86 exhibited more than 1000-fold selectivity for PDE V over the other four PDE isozymes. In addition, cGMP-PDE inhibitors 64, 65, and 73 were found to have an additional property of thromboxane synthesis inhibitory activity.
Discovery of Potent Cyclic GMP Phosphodiesterase Inhibitors. 2-Pyridyl-and 2-Imidazolylquinazolines Possessing Cyclic GMP Phoshodiesterase and Thromboxane Synthesis Inhibitory Activities. -The structure of 2-phenyl-4-anilinoquinazoline, identified as moderate cyclic GMP phosphodiesterase (cGMP-PDE, PDE V) inhibitor, is modified ( ca. 70 examples) at the 2-, 4-, and 6-positions of the quinazoline ring, as demonstrated by derivatives of types (VII), (XI), (XIV), and ( XV). The 6-substituted quinazolines, e.g. (XVb) and (XVc), are 1000 times more potent with respect to their cGMP-PDE V inhibitory activity than the known inhibitor zaprinast. The cGMP-PDE inhibitors (VII), (XI) , and (XVa) also show thromboxane synthesis inhibitory activity. -(LEE, S. J.; KONISHI, Y.; YU, D. T.; MISKOWSKI, T. A.; RIVIELLO, C. M.; MACINA, O. T.; FRIERSON, M. R.; KONDO, K.; SUGITANI, M.; SIRCAR, J. C.; BLAZEJEWSKI, K. M.; J.
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