title: Insights into structure-activity relationships from lipophilicity profiles of pyridin-2(1H)-one analogs of the cardiotonic agent milrinone.
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.
authors.affiliation: Dipartimento Farmaco-chimico, Università degli Studi, via Orabona 4, 70125 Bari, Italy.
authors.forename: Modesto
authors.initials: M
authors.lastname: de Candia
authors.forename: Paola
authors.initials: P
authors.lastname: Fossa
authors.forename: Saverio
authors.initials: S
authors.lastname: Cellamare
authors.forename: Luisa
authors.initials: L
authors.lastname: Mosti
authors.forename: Angelo
authors.initials: A
authors.lastname: Carotti
authors.forename: Cosimo
authors.initials: C
authors.lastname: Altomare
mesh_terms: D020003:1-Octanol; D002316:Cardiotonic Agents / Q000138:chemical synthesis / Q000737:chemistry*; D002725:Chloroform; D006863:Hydrogen-Ion Concentration; D020105:Milrinone / Q000737:chemistry*; D011199:Potentiometry; D011728:Pyridones / Q000138:chemical synthesis / Q000737:chemistry*; D012995:Solubility; D012997:Solvents; D013329:Structure-Activity Relationship; D014867:Water
chemical_list: D002316:Cardiotonic Agents; D011728:Pyridones; D012997:Solvents; D014867:Water; D002725:Chloroform; D020105:Milrinone; D020003:1-Octanol