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.
Insights into structure–activity relationships from lipophilicity profiles of pyridin-2(1H)-one analogs of the cardiotonic agent milrinon
DE CANDIA, MODESTO;CELLAMARE, Saverio;CAROTTI, Angelo;ALTOMARE, Cosimo Damiano
2005-01-01
Abstract
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.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
