Ionization behaviour and tautomerism-dependent lipophilicity of pyridine-2(1H)-one cardiotonic agents

The acid-base properties of pyridine-2(1H)-one derivatives, analogues of th e cardiotonic agent milrinone, were studied by capillary zone electrophores is (CZE). Electrophoretic mobility and pH data were fitted to equilibrium e xpressions and apparent dissociation constants (pK(a)) calculated by non-li near regression. Compared with the ultraviolet (UV) spectrophotometric meth od and potentiometric titrations. the CZE technique showed advantages, such as rapidity and applicability to compounds that are sparingly soluble in w ater. Based on the pK(a) values, intramolecular electronic interactions wer e assessed. The lipophilicity of a number of derivatives was also examined, by determining their n-octanol/water distribution coefficients over a wide pH range, and found to be significantly affected by 2-pyridone/2-hydroxypy ridine tautomerism. As revealed by a comparison between experimental and ca lculated log P values, electron withdrawing substituents, especially at the C(6) position of 2-pyridone, favour the less polar hydroxypyridine tautome rs both in water and octanol. Our results indicate that the positive inotro pism of milrinone-related compounds could be explained taking ionization an d tautomerism into account. (C) 2000 Elsevier Science Ltd. All rights reser ved.