226992-16-1Relevant academic research and scientific papers
New p-methylsulfonamido phenylethylamine analogues as class III antiarrhythmic agents: Design, synthesis, biological assay, and 3D-QSAR analysis
Liu, Hong,Ji, Ming,Luo, Xiaomin,Shen, Jianhua,Huang, Xiaoqin,Hua, Weiyi,Jiang, Hualiang,Chen, Kaixian
, p. 2953 - 2969 (2007/10/03)
Class III antiarrhythmic agents selectively delay the effective refractory period (ERP) and increase the transmembrance 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-1). 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 × 10-8 mol/L in increasing ERP by 10 ms, slightly less potent than that of 2, 1.1 × 10-8 mol/L. Compound 4a also produced a slightly lower change in ERP at 10-5 M, ΔERP% = 17.5% (ΔERP% = 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, r2 = 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 × 10-8mol/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.
Computer-aided design, synthesis and biological assay of p-methylsulfonamido phenylethylamine analogues
Liu, Hong,Ji, Min,Jiang, Hualiang,Liu, Ligang,Hua, Weiyi,Chen, Kaixian,Ji, Ruyun
, p. 2153 - 2157 (2007/10/03)
Class III antiarrhythmic agents selectively delay the effective refractory period (ERP) and increase the transmembrance action potential duration (APD). Based on our previous studies, a set of 17 methylsulfonamido phenylethylamine analogues were investigated by 3D-QSAR techniques of CoMFA and CoMSIA. 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. According to the clues provided by this 3D-QSAR analysis, we designed and synthesized a series of new analogues of methanesulfonamido phenylethylamine (VI(a-i)). Pharmacological assay indicated that the effective concentrations of delaying the functional refractory period (FRP) 10ms of these new compounds have a good correlation with the 3D-QSAR predicted values. It is remarkable that the maximal percent change of delaying FRP in μM of compound VI(c) is much higher than that of dofetilide. The results showed that the 3D-QSAR models are reliable. (C) 2000 Elsevier Science Ltd.
