Quantitative relationships between the structure and pharmacokinetic parameters of several compounds have been derived using the molecular connectivity approach. The correlation coefficients of equations obtained using the Chi indices (chi) as predictor parameters were compared favorably with those obtained by the linear free energy approach, where physicochemical parameters have been used as predictor variables. High correlation coefficients (r) for the first-order elimination rate constant (r = 0.86), total body clearance (r = 0.89), and protein binding association constant (r = 0.78) for substituted 2-sulfapyridines were obtained. However, including the pKa (indicative of electronic effects) of the compounds within the equation as a predictor variable caused an increase in the correlation coefficients.

We have compared the ED50 value for antiarrhythmic activity and the acute toxicities in mice of quinidine and 4 recently synthesized analogs. For the ED50 studies, groups of mice were treated intravenously with equally spaced logarithmic doses of 6'-methoxycinchonine (quinidine), 6'-hydroxycinchonine (cupreidine), 6'-isovaleryloxycinchonine, 6'-acetyloxycinchonine and 6'-benzoyloxycinchonine. For the actue toxicity studies, mice were treated intraperitoneally with quinidine and the 4 analogs. Mice were observed over a 24-h period, and thereafter for each additional 24-h period for a total of 120 h. Tests for parallelism of acute toxicity indicated that with the exception of the 6'-isovaleryloxy derivative the drug treatment regression lines were parallel to that of quinidine (P > 0.05). The results indicated decreases of 50% (843 mumol/kg), 52% (857 mumol/kg), and 61% (910 mumol/kg) in the acute toxicities of the 6'-acetyloxy, 6'-hydroxy, and 6'-benzoyloxycinchonine, respectively. The 6'-acetyloxy (18.5 mumol/kg) and 6'-benzoyloxy (14.6 mumol/kg) derivatives had significantly lower ED50 values than quinidine (60.1 mumol/kg). The results suggest that the 6'-acetyloxy and 6'-benzoyloxy derivatives may have much greater antiarrhythmic effectiveness than quinidine.