Physicochemical profiling of new aminopropan-2-ol derivatives with beta-adrenolytic activity: the importance for pharmacokinetic properties.

A convenient procedure has been developed for the determination of dissociation constants (pKa) and partition (log P) and distribution (log D) coefficients of three new aminopropan-2-ol derivatives with beta-adrenolytic activity briefly called 2F109, ANBL and TWo8. The apparent acid dissociation constant (psKa) in these water-insoluble compounds was determined potentiometrically in dimethylformamide-water, dimethyl sulfoxide-water and methanol-water mixtures at a temperature of 25 degrees C. The aqueous pKa values assessed by Yasuda-Shedlovsky extrapolation were 8.64 +/- 0.06, 8.85 +/- 0.51 and 8.26 +/- 0.45 for 2F109, ANBL and TWo8, respectively. Lipophilicity expressed by chromatographic retention factor was determined by reversed phase liquid chromatography at pH 10.5 using a Zorbax Extend C18 column (log k10.5), and at pH 7.4 using an immobilized artificial membrane IAM.PC.DD2 column (log k7.4), respectively. The log k of each compound extrapolated to 100% aqueous phase (log kw10.5 and and log kw7.4) were corrected with log P and log D of acebutolol, atenolol, metoprolol,pindolol, propranolol and sotalol used as the model drugs.