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Insights Into Structure-Activity Relationships From Lipophilicity Profiles of pyridin-2(1H)-one Analogs of the Cardiotonic Agent Milrinone

Insights Into Structure-Activity Relationships From Lipophilicity Profiles of pyridin-2(1H)-one Analogs of the Cardiotonic Agent Milrinone

Modesto de Candia, Paola Fossa, Saverio Cellamare, Luisa Mosti, Angelo Carotti, Cosimo Altomare

Eur J Pharm Sci. 2005 Sep;26(1):78-86.

PMID: 15955679

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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP62749262	Amrinone Related Compound C		62749-26-2	Price

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