Development of pharmacophores for inhibitors of the rapid component of the cardiac delayed rectifier potassium current

Blockade of cardiac-delayed rectifier potassium current (I_Kr) is an important mechanism for Class III antiarrhythmic effect. We developed pharmacophores for I_Kr inhibitors starting from structures of known blockers. To obtain the pharmacophores, DISCO module of SYBYL was used. Conformations required for DISCO computations were provided by Multisearch type conformational analyses. A common five-point three-dimensional relationship was identified for the most active compounds, whereas a four-point pharmacophore forming a subset of the former one, could be developed for less potent agents. © 1998 John Wiley & Sons, Inc. Int J Quant Chem 69: 21–30, 1998