Key result
Novel p-methylsulfonamido phenylethylamine analogue 6c significantly increases atrial effective refractory period in preclinical models.
Why the study?
Class III antiarrhythmic agents selectively delay ERP and increase APD, but new analogues with improved activity and predictive design models are needed.
3D-QSAR models successfully guided the design of new p-methylsulfonamido phenylethylamine analogues that demonstrate potent Class III antiarrhythmic activity in isolated animal atria.
May support preclinical development of class III agents; leaves open translation to human antiarrhythmic use.
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.
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Liu et al. (2002) studied this question. p-Methylsulfonamido phenylethylamine analogues vs. Dofetilide was evaluated on Effective refractory period (ERP) increase. Newly synthesized p-methylsulfonamido phenylethylamine analogues, particularly compound 6c, demonstrated significant activity in increasing the effective refractory period in isolated animal atria.
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