抗心律失常药对甲苯磺胺苯乙胺类化合物的设计合成和生物活性和3D-QSAR分析
III类抗心律失常剂有选择地延迟有效不应期（ERP）和增加跨膜动作电位持续时间（APD）。使用多非利特（2），为III类抗心律失常剂的模板，我们设计并合成了16甲基磺酰氨基苯乙胺类似物（图4a-d和图5a-1）。药理试验表明，所有这些化合物显示出活性增加了ERP中分离动物心房;其中，化合物4a的有效浓度为1.6×10（-8）摩尔/升的由10毫秒增加的ERP，比2，1.1×10（-8）mol / L的略少强效。化合物4a也产生了ERP在10（-5）M，DeltaERP％= 17.5％，稍低的变化（DeltaERP％= 24.0％为多非利特）。在此生物测定结果的基础上，这16个化合物与多非利特一起由三维定量构效关系（3D-QSAR）比较分子场分析技术（的CoMFA），比较分子相似性指数分析（指数分析）进行了调查，和全息图的QSAR（HQSAR）。三维定量构效关系模型进行了测试与另外11个化合物（4E-H和5M-S），我们以后合成。结果表明，的CoMFA，指数分析，和HQSAR预测为11新合成的化合物具有良好的相关性与实验值的活动，R（2）= 0.943，0.891和0.809的三个QSAR模型，分别。这表明，在3D QSAR模型证明了良好的预测能力，并能描述的立体，静电，并为受体位点的识别力疏水要求。在这些成果的基础上，我们设计并根据三维定量构效关系分析提供的线索合成甲基磺酰phenylethyamine（6A-H）的另外八个新的类似物。药理试验表明，有效浓度由10毫秒的这些与三维构效关系相关以及新设计的化合物延迟了ERP的预测值。值得注意的是，延迟的ERP在的百分比变化图10（-5）M化合物6c为比多非利特的高得多;化合物6c的有效浓度为5.0×10（-8）摩尔/升的由10毫秒，这是比2稍低的结果表明，在3D-QSAR模型是可靠的，并且可以延伸到增加了ERP设计新的抗心律失常药物。
New p-methylsulfonamido phenylethylamine analogues as class III antiarrhythmic agents: design, synthesis, biological assay, and 3D-QSAR analysis.
Liu H; Ji M; Luo X; Shen J; Huang X; Hua W; Jiang H; Chen K.
J Med Chem; 45(14): 2953-69, 2002 Jul 4.
Class III antiarrhythmic agents selectively delay the effective refractory period (ERP) and increase the transmembrane action potential duration (APD). Using dofetilide (2) as a template of class III antiarrhythmic agents, we designed and synthesized 16 methylsulfonamido phenylethylamine analogues (4a-d and 5a-l). Pharmacological assay indicated that all of these compounds showed activity for increasing the ERP in isolated animal atrium; among them, the effective concentration of compound 4a is 1.6 x 10(-8) mol/L in increasing ERP by 10 ms, slightly less potent than that of 2, 1.1 x 10(-8) mol/L. Compound 4a also produced a slightly lower change in ERP at 10(-5) M, DeltaERP% = 17.5% (DeltaERP% = 24.0% for dofetilide). On the basis of this bioassay result, these 16 compounds together with dofetilide were investigated by the three-dimensional quantitative structure-activity relationship (3D-QSAR) techniques of comparative molecular field analysis (CoMFA), comparative molecular similarity index analysis (CoMSIA), and the hologram QSAR (HQSAR). The 3D-QSAR models were tested with another 11 compounds (4e-h and 5m-s) that we synthesized later. Results revealed that the CoMFA, CoMSIA, and HQSAR predicted activities for the 11 newly synthesized compounds that have a good correlation with their experimental value, r(2) = 0.943, 0.891, and 0.809 for the three QSAR models, respectively. This indicates that the 3D-QSAR models proved a good predictive ability and could describe the steric, electrostatic, and hydrophobic requirements for recognition forces of the receptor site. On the basis of these results, we designed and synthesized another eight new analogues of methanesulfonamido phenylethyamine (6a-h) according to the clues provided by the 3D-QSAR analyses. Pharmacological assay indicated that the effective concentrations of delaying the ERP by 10 ms of these newly designed compounds correlated well with the 3D-QSAR predicted values. It is remarkable that the percent change of delaying ERP at 10(-5) M compound 6c is much higher than that of dofetilide; the effective concentration of compound 6c is 5.0 x 10(-8)mol/L in increasing the ERP by 10 ms, which is slightly lower than that of 2. The results showed that the 3D-QSAR models are reliable and can be extended to design new antiarrhythmic agents.
