Insights into structure–activity relationships from lipophilicity profiles of pyridin-2(1H)-one analogs of the cardiotonic agent milrinone
| Autor: | Paola Fossa, Angelo Carotti, Cosimo Altomare, Saverio Cellamare, Modesto de Candia, Luisa Mosti |
|---|---|
| Rok vydání: | 2005 |
| Předmět: |
Cardiotonic Agents
Pyridones Stereochemistry Pharmaceutical Science Pyridin-2(1H)-one Analogs Structure-Activity Relationships Lipophilicity Profiles Structure-Activity Relationship medicine Potency Partition (number theory) biology Chemistry Water 1-Octanol Hydrogen-Ion Concentration Into-structure Tautomer Partition coefficient Solubility Enzyme inhibitor Lipophilicity Potentiometry Solvents biology.protein Milrinone Chloroform medicine.drug |
| Zdroj: | European Journal of Pharmaceutical Sciences. 26:78-86 |
| ISSN: | 0928-0987 |
| DOI: | 10.1016/j.ejps.2005.05.001 |
| Popis: | 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 (log PN) 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 (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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Full Text from ScienceDirect