Evaluation of the desferrithiocin pharmacophore as a vector for hydroxamates.
A series of (S)-desmethyldesferrithiocin (DMDFT, 1) hydroxamates and a bis-salicyl polyether hydroxamate are evaluated for their iron-clearing properties in rodents; some of these are further assessed in primates. These hydroxamates include (S)-desmethyldesferrithiocin, N-methylhydroxamate (2); (S)-desmethyldesferrithiocin, N-[5-(acetylhydroxyamino)pentyl]hydroxamate (3); desmethyldesferrithiocin, N-benzylhydroxamate (4); (S,S)-N(1), N(8)-bis[4,5-dihydro-2-(3-hydroxy-2-pyridinyl)-4-thiazoyl]-N(1), N(8)-dihydroxy-3,6-dioxa-1,8-octanediamine (5); and N(1), N(8)-bis(2-hydroxybenzoyl)-N(1),N(8)-dihydroxy-3,6-dioxa-1, 8-octanediamine (6). The ligands are evaluated when given both orally (po) and subcutaneously (sc) in the bile-duct-cannulated rodent model. In iron-overloaded primates, ligands 1-4 are assessed when administered po and sc. The efficiencies of the hydroxamates are shown to vary considerably; giving the compounds sc consistently resulted in greater chelating efficiency in vivo. After oral administration in the primate, compound 3, a pentacoordinate unsymmetrical dihydroxamate, produces iron excretion sufficient to warrant further preclinical evaluation both as a potential orally active iron-chelating agent and as a parenteral iron chelator. The increased iron clearance of several of these ligands when administered sc versus po also underscores the idea that parenteral administration is a reasonable alternative to a less efficient, orally active device which would require large and frequent doses.
Bergeron
R J
RJ
Department of Medicinal Chemistry, University of Florida, Gainesville, Florida 32610-0485, USA.
McManis
J S
JS
Bussenius
J
J
Brittenham
G M
GM
Wiegand
J
J
D000284:Administration, Oral; D000818:Animals; D002428:Cebus; D004095:Dihydropyridines / Q000737:chemistry* / Q000494:pharmacology; D004353:Drug Evaluation, Preclinical; D006877:Hydroxamic Acids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D007279:Injections, Subcutaneous; D007502:Iron Chelating Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity; D019190:Iron Overload / Q000188:drug therapy; D008024:Ligands; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis* / Q000737:chemistry* / Q000494:pharmacology
D004095:Dihydropyridines; D006877:Hydroxamic Acids; D007502:Iron Chelating Agents; D008024:Ligands; D013844:Thiazoles; C120792:desmethyldesferrithiocin N-(5-(acetylhydroxyamino)pentyl)hydroxamate; C050223:desferrithiocin