Computer-aided design, synthesis and biological assay of p-methylsulfonamido phenylethylamine analogues

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 (VIa-i). Pharmacological assay indicated that the effective concentrations of delaying the functional refractory period (FRP) 10 ms 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 mu M of compound VIc is much higher than that of dofetilide. The results showed that the 3D-QSAR models are reliable. (C) 2000 Elsevier Science Ltd. All rights reserved.