de Candia Modesto, Fossa Paola, Cellamare Saverio, Mosti Luisa, Carotti Angelo, Altomare Cosimo
Dipartimento Farmaco-chimico, Università degli Studi, via Orabona 4, 70125 Bari, Italy.
Eur J Pharm Sci. 2005 Sep;26(1):78-86. doi: 10.1016/j.ejps.2005.05.001.
The pH-dependent distribution profiles of a series of pyridin-2(1H)-one analogs of the inotropic/vasodilator agent milrinone, determined in 1-octanol/water (and for a number of them also in chloroform-water) using a pH-metric technique, showed that partition coefficients of the neutral forms (logP(N)) significantly encode for 2-pyridone/2-hydroxypyridine tautomerism. A comparison between experimental and calculated logP (CLOG P) values indicated that electron-withdrawing substituents, at the C(6) position, and to a lesser extent at the C(3) and C(5) positions, push up logPs toward the values of the more lipophilic 2-hydroxypyridine tautomers. RP-HPLC parameters (log k'omega) carry for large part similar information related to tautomerism-dependent lipophilicity, but they were also found to reasonably correlate with the solute molar volumes (r2 = 0.75). Investigating the implications of ionization and partition properties in modulating the in vitro cardiotonic activity of the examined compounds revealed that a high fraction of the neutral species at physiological pH, predominantly in the more polar pyridone (OX) tautomer, increases the positive inotropic potency.
采用pH测定技术，在1-辛醇/水体系中（部分化合物还在氯仿-水体系中）测定了强心/血管扩张剂米力农一系列吡啶-2(1H)-酮类似物的pH依赖性分布情况，结果表明中性形式的分配系数（logP(N)）显著反映了2-吡啶酮/2-羟基吡啶互变异构现象。实验测得的logP值与计算得到的logP（CLOG P）值之间的比较表明，C(6)位以及程度稍小的C(3)和C(5)位上的吸电子取代基会使logP值升高，趋向于更具亲脂性的2-羟基吡啶互变异构体的值。反相高效液相色谱参数（log k'omega）在很大程度上携带了与互变异构依赖性亲脂性相关的类似信息，但也发现它们与溶质摩尔体积具有合理的相关性（r2 = 0.75）。研究电离和分配性质对所研究化合物体外强心活性的影响表明，在生理pH下，大部分中性物种主要以极性更强的吡啶酮（OX）互变异构体形式存在时，会增强正性肌力作用。
