Document Detail

The design, synthesis, and evaluation of organ-specific iron chelators.
MedLine Citation:
PMID:  17125256     Owner:  NLM     Status:  MEDLINE    
A series of iron chelators, three (S)-4,5-dihydro-2-(2-hydroxyphenyl)-4-methyl-4-thiazolecarboxylic acid (DADFT) and three (S)-4,5-dihydro-2-(2-hydroxyphenyl)-4-thiazolecarboxylic acid (DADMDFT) analogues are synthesized and assessed for their lipophilicity (log Papp), iron-clearing efficiency (ICE) in rodents and iron-loaded primates (Cebus apella), toxicity in rodents, and organ distribution in rodents. The results lead to a number of generalizations useful in chelator design strategies. In rodents, while log Papp is a good predictor of a chelator's ICE, chelator liver concentration is a better tool. In primates, log Papp is a good predictor of ICE, but only when comparing structurally very similar chelators. There is a profound difference in toxicity between the DADMDFT and DADFT series: DADMDFTs are less toxic. Within the DADFT family of ligands, the more lipophilic ligands are generally more toxic. Lipophilicity can have a profound effect on ligand organ distribution, and ligands can thus be targeted to organs compromised in iron overload disease, for example, the heart.
Raymond J Bergeron; Jan Wiegand; James S McManis; Neelam Bharti
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural    
Journal Detail:
Title:  Journal of medicinal chemistry     Volume:  49     ISSN:  0022-2623     ISO Abbreviation:  J. Med. Chem.     Publication Date:  2006 Nov 
Date Detail:
Created Date:  2006-11-27     Completed Date:  2007-02-15     Revised Date:  2012-02-08    
Medline Journal Info:
Nlm Unique ID:  9716531     Medline TA:  J Med Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  7032-43     Citation Subset:  IM    
Department of Medicinal Chemistry, University of Florida, Gainesville, Florida 32610-0485, USA.
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MeSH Terms
Bile / metabolism
Carboxylic Acids / chemical synthesis*,  chemistry,  pharmacology
Dihydropyridines / chemical synthesis,  chemistry,  pharmacology
Iron Chelating Agents / chemical synthesis*,  chemistry,  pharmacology
Iron-Dextran Complex / blood,  pharmacokinetics,  urine
Kidney / metabolism
Liver / metabolism
Myocardium / metabolism
Organ Specificity
Pancreas / metabolism
Rats, Sprague-Dawley
Structure-Activity Relationship
Thiazoles / chemical synthesis*,  chemistry,  pharmacology
Tissue Distribution
Grant Support
R37 DK049108-11/DK/NIDDK NIH HHS; R37 DK049108-11S1/DK/NIDDK NIH HHS; R37-DK49108/DK/NIDDK NIH HHS
Reg. No./Substance:
0/Carboxylic Acids; 0/Dihydropyridines; 0/Iron Chelating Agents; 0/Thiazoles; 0/desazadesferrithiocin; 9004-66-4/Iron-Dextran Complex

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