Department of Chemistry, School of Sciences, Islamic Azad University, Ahvaz Branch, Ahvaz, 61349-68875, Islamic Republic of Iran.
Bioorg Med Chem. 2010 Jan 15;18(2):855-62. doi: 10.1016/j.bmc.2009.11.044. Epub 2009 Nov 26.
Selective PDE3 (phosphodiesterase 3) inhibitors improve cardiac contractility and may be used in congestive heart failure. However, their proarrhythmic potential is the most important side effect. In this work ten new synthetic compounds (3-[(4-methyl-2-oxo-1,2-dihydro-6-quinolinyl)oxy]methylbenzamide analogs: 4a-j) were designed, synthesized and tested for the inhibitory activity against human PDE3A and PDE3B. The strategy of the design was based on the structure of vesnarinone (a selective PDE3 inhibitor) and its docking analysis results. The synthetic compounds showed better PDE3 inhibitory activity in comparison with vesnarinone. Using docking analysis, a common binding model of each compound toward PDE3 was suggested. In the next step the potential cardiotonic activity of the best PDE3A inhibitors (4b, IC(50)=0.43+/-0.04microM) was evaluated by using the spontaneously beating atria model. In the experiment, atrium of reserpine-treated rat was isolated and the contractile and chronotropic effects of the synthetic compound were assessed. That was carried out in comparison with vesnarinone. The best pharmacological profile was obtained for the compound 4b, which displayed selectivity for increasing the force of contraction (46+/-3% change over the control) rather than the frequency rate (16+/-4% change over the control) at 100microM.
选择性磷酸二酯酶 3（PDE3）抑制剂可改善心肌收缩力，可用于充血性心力衰竭。然而，其致心律失常的潜力是最重要的副作用。在这项工作中，设计、合成了十种新的合成化合物（3-[(4-甲基-2-氧代-1,2-二氢-6-喹啉基)氧基]甲基苯甲酰胺类似物：4a-j），并测试了它们对人 PDE3A 和 PDE3B 的抑制活性。设计的策略基于 vesnarinone（一种选择性 PDE3 抑制剂）的结构及其对接分析结果。与 vesnarinone 相比，合成化合物显示出更好的 PDE3 抑制活性。通过对接分析，提出了每个化合物与 PDE3 的共同结合模型。在下一步中，通过使用自发跳动心房模型评估了最佳 PDE3A 抑制剂（4b，IC50=0.43+/-0.04μM）的潜在正性肌力作用。在实验中，分离了利血平处理的大鼠心房，并评估了合成化合物的收缩和变时作用。与 vesnarinone 进行了比较。在 100μM 时，化合物 4b 显示出增加收缩力的选择性（相对于对照增加 46+/-3%）而不是频率率（相对于对照增加 16+/-4%），获得了最佳的药理特性。
