PMID- 18533709
OWN - NLM
STAT- MEDLINE
DCOM- 20080812
LR  - 20240312
IS  - 1520-4804 (Electronic)
IS  - 0022-2623 (Print)
IS  - 0022-2623 (Linking)
VI  - 51
IP  - 13
DP  - 2008 Jul 10
TI  - Design, synthesis, and testing of non-nephrotoxic desazadesferrithiocin polyether 
      analogues.
PG  - 3913-23
LID - 10.1021/jm800154m [doi]
AB  - A series of iron-clearing efficiencies (ICEs), ferrokinetics, and toxicity 
      studies for ( 
      S)-2-(2,4-dihydroxyphenyl)-4,5-dihydro-4-methyl-4-thiazolecarboxylic acid 
      (deferitrin, 1), ( 
      S)-4,5-dihydro-2-[2-hydroxy-4-(3,6,9-trioxadecyloxy)phenyl]-4-methyl-4-thiazolecarboxylic 
      acid ( 2), and 
      (S)-4,5-dihydro-2-[2-hydroxy-3-(3,6,9-trioxadecyloxy)phenyl]-4-methyl-4-thiazolecarboxylic 
      acid ( 3) are reported. The ICEs in rodents are shown to be dose-dependent and 
      saturable for ligands 2 and 3 and superior to 1. Both polyether analogues in 
      subcutaneous (sc) versus oral (po) administration in rodents and primates 
      demonstrated excellent bioavailability. Finally, in a series of toxicity studies 
      of ligands 1- 3, the dosing regimen was shown to have a profound effect in 
      animals treated with ligand 1. When ligand 1 was given at doses of 237 
      micromol/kg/day twice a day (b.i.d.), there was serious proximal tubule damage 
      versus 474 micromol/kg/day once daily (s.i.d.). With 2 and 3, in iron-overloaded 
      and/or non-iron-loaded rodents, kidney histopathologies remained normal.
FAU - Bergeron, Raymond J
AU  - Bergeron RJ
AD  - Department of Medicinal Chemistry, University of Florida, Gainesville, Florida 
      32610-0485, USA. rayb@ufl.edu
FAU - Wiegand, Jan
AU  - Wiegand J
FAU - McManis, James S
AU  - McManis JS
FAU - Bharti, Neelam
AU  - Bharti N
FAU - Singh, Shailendra
AU  - Singh S
LA  - eng
GR  - R37 DK049108/DK/NIDDK NIH HHS/United States
GR  - R37 DK049108-13/DK/NIDDK NIH HHS/United States
GR  - R37DK049108/DK/NIDDK NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20080606
PL  - United States
TA  - J Med Chem
JT  - Journal of medicinal chemistry
JID - 9716531
RN  - 0 (Dihydropyridines)
RN  - 0 (Iron Chelating Agents)
RN  - 0 (Thiazoles)
RN  - 0 (desazadesferrithiocin)
RN  - 0F5N573A2Y (Ether)
RN  - E1UOL152H7 (Iron)
SB  - IM
MH  - Animals
MH  - Biliary Tract/drug effects/metabolism
MH  - Cercopithecus
MH  - Dihydropyridines/*chemical synthesis/chemistry/*pharmacology
MH  - *Drug Design
MH  - Ether/*chemistry
MH  - Iron/metabolism
MH  - Iron Chelating Agents/chemical synthesis/chemistry/pharmacology
MH  - Kidney/drug effects
MH  - Kinetics
MH  - Male
MH  - Molecular Structure
MH  - Rats
MH  - Structure-Activity Relationship
MH  - Thiazoles/*chemical synthesis/chemistry/*pharmacology
PMC - PMC2759697
MID - NIHMS122079
EDAT- 2008/06/07 09:00
MHDA- 2008/08/13 09:00
PMCR- 2009/10/09
CRDT- 2008/06/07 09:00
PHST- 2008/06/07 09:00 [pubmed]
PHST- 2008/08/13 09:00 [medline]
PHST- 2008/06/07 09:00 [entrez]
PHST- 2009/10/09 00:00 [pmc-release]
AID - 10.1021/jm800154m [doi]
PST - ppublish
SO  - J Med Chem. 2008 Jul 10;51(13):3913-23. doi: 10.1021/jm800154m. Epub 2008 Jun 6.