Insights into structure–activity relationships from lipophilicity profiles of pyridin-2(1 H)-one analogs of the cardiotonic agent milrinone

Abstract

The pH-dependent distribution profiles of a series of pyridin-2(1 H)-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 (log P N ) significantly encode for 2-pyridone/2-hydroxypyridine tautomerism. A comparison between experimental and calculated log P (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 log Ps toward the values of the more lipophilic 2-hydroxypyridine tautomers. RP-HPLC parameters ( log k ′ w ) carry for large part similar information related to tautomerism-dependent lipophilicity, but they were also found to reasonably correlate with the solute molar volumes ( r 2 = 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.