QUANTITATIVE STRUCTURE ACTIVITY RELATIONSHIP STUDY OF ANTIARRHYTHMIC PHENYLPYRIDINES USING MULTIVARIATE PARTIAL LEAST-SQUARES MODELING

The partial least squares (PLS) method was applied to a study of antiarrhythmic activity data of phenylpyridines. A two-component PLS model based on three physicochemical parameters successfully separated active from inactive compounds. Since the modelling power of each physicochemical parameter is great enough, these coefficients of the PLS model equation are interpreted as measures of the contribution of physicochemical parameters. From the PLS discriminant function, a more potent antiarrhythmic agent can be produced by increasing the molar refractivity value of a substituent R on the benzene ring, increasing the torsion angle between amide function and the benzene ring and decreasing the proton affinity of an amino group of a phenylpyridine. The PLS model equation corresponds to the modulated-receptor hypothesis proposed by Hille as a mechanism for the antiarrhythmic agent-action for sodium channels. The PLS method has proved to be more predictive and promising in multivariate statistical methods for quantitative structure-activity relationship analysis than a linear learning machine approach.