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

被引：37

作者：

LEE, SJ ^{[1
]}

KONISHI, Y ^{[1
]}

YU, DT ^{[1
]}

MISKOWSKI, TA ^{[1
]}

RIVIELLO, CM ^{[1
]}

MACINA, OT ^{[1
]}

FRIERSON, MR ^{[1
]}

KONDO, K ^{[1
]}

SUGITANI, M ^{[1
]}

SIRCAR, JC ^{[1
]}

BLAZEJEWSKI, KM ^{[1
]}

机构：

[1] ONO PHARMACEUT CO LTD,MINASE RES INST,OSAKA,JAPAN

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 1995年 / 38卷 / 18期

关键词：

D O I：

10.1021/jm00018a014

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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 assay 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.

引用

页码：3547 / 3557

页数：11

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