Cyclic GMP phosphodiesterase inhibitors. 2. Requirement of 6-substitution of quinazoline derivatives for potent and selective inhibitory activity.
Cyclic GMP phosphodiesterase inhibitors. 2. Requirement of 6-substitution of quinazoline derivatives for potent and selective inhibitory activity.
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DOI：
10.1021/jm00039a024
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发表时间：
1994-06
影响因子：
7.3
通讯作者：
Y. Takase;T. Saeki;N. Watanabe;H. Adachi;S. Souda;I. Saito
中科院分区：
文献类型：
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作者：
Y. Takase;T. Saeki;N. Watanabe;H. Adachi;S. Souda;I. Saito
我们合成了各种 5 至 8 位取代的 4-[[3,4-(亚甲二氧基)苄基]氨基]喹唑啉，并评估了它们对猪主动脉环 GMP 磷酸二酯酶 (cGMP-PDE) 的抑制活性。 6 位的单取代对于抑制活性至关重要，优选的取代基是紧凑且疏水的：甲氧基（3b，IC50 = 0.23 µM）、甲基（3c，0.10 µM）、氯（3d，0.019 µM）、硫甲基（3f，0.031 µM）和氰基（3p，0.090 µM）基团。化合物3b-d、f、p对其他PDE同工酶缺乏抑制活性（所有IC50值> 100 microM），并且它们在猪冠状动脉中的舒张活性与对cGMP-PDE的抑制活性密切相关（r = 0.88，p < 0.05）。其中一种化合物 3b 提高了离体猪冠状动脉的细胞内 cGMP 水平，但不引起 cAMP 水平的任何变化。我们认为该系列化合物通过有效且特异性地抑制 cGMP-PDE 来扩张冠状动脉。
We synthesized various 4-[[3,4-(methylenedioxy)benzyl]amino]quinazolines substituted at the 5- to 8-positions and evaluated their inhibitory activities toward cyclic GMP phosphodiesterase (cGMP-PDE) from porcine aorta. Monosubstitution at the 6-position was essential for the inhibitory activity, and the preferred substituents were compact and hydrophobic: methoxy (3b, IC50 = 0.23 microM), methyl (3c, 0.10 microM), chloro (3d, 0.019 microM), thiomethyl (3f, 0.031 microM), and cyano (3p, 0.090 microM) groups. Compounds 3b-d,f,p lacked inhibitory activity toward other PDE isozymes (all IC50 values > 100 microM), and their relaxing activities in porcine coronary arteries were well correlated with the inhibitory activities toward cGMP-PDE (r = 0.88, p < 0.05). One of these compounds, 3b, elevated the intracellular cGMP level in isolated porcine coronary arteries without causing any change in the cAMP level. We consider that this series of compounds dilates coronary arteries via potent and specific inhibition of cGMP-PDE.