Document Detail

Insights into structure-activity relationships from lipophilicity profiles of pyridin-2(1H)-one analogs of the cardiotonic agent milrinone.
MedLine Citation:
PMID:  15955679     Owner:  NLM     Status:  MEDLINE    
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.
Modesto de Candia; Paola Fossa; Saverio Cellamare; Luisa Mosti; Angelo Carotti; Cosimo Altomare
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Publication Detail:
Type:  Comparative Study; Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences     Volume:  26     ISSN:  0928-0987     ISO Abbreviation:  Eur J Pharm Sci     Publication Date:  2005 Sep 
Date Detail:
Created Date:  2005-08-08     Completed Date:  2006-04-07     Revised Date:  2006-11-15    
Medline Journal Info:
Nlm Unique ID:  9317982     Medline TA:  Eur J Pharm Sci     Country:  Netherlands    
Other Details:
Languages:  eng     Pagination:  78-86     Citation Subset:  IM    
Dipartimento Farmaco-chimico, Università degli Studi, via Orabona 4, 70125 Bari, Italy.
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MeSH Terms
Cardiotonic Agents / chemical synthesis,  chemistry*
Hydrogen-Ion Concentration
Milrinone / chemistry*
Pyridones / chemical synthesis,  chemistry*
Structure-Activity Relationship
Reg. No./Substance:
0/Cardiotonic Agents; 0/Pyridones; 0/Solvents; 111-87-5/1-Octanol; 67-66-3/Chloroform; 7732-18-5/Water; 78415-72-2/Milrinone

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