Prodrug thiamine analogs as inhibitors of the enzyme transketolase.
Bioorg Med Chem Lett
; 18(2): 505-8, 2008 Jan 15.
Article
en En
| MEDLINE
| ID: mdl-18083562
ABSTRACT
Transketolase, a key enzyme in the pentose phosphate pathway, has been suggested as a target for inhibition in the treatment of cancer. Compound 5a ('N3'-pyridyl thiamine'; 3-(6-methyl-2-amino-pyridin-3-ylmethyl)-5-(2-hydroxy-ethyl)-4-methyl-thiazol-3-ium chloride hydrochloride), an analog of the transketolase cofactor thiamine, is a potent transketolase inhibitor but suffers from poor pharmacokinetics due to high clearance and C(max) linked toxicity. An efficient way of improving the pharmacokinetic profile of 5a is to prepare oxidized prodrugs which are slowly reduced in vivo yielding longer, sustained blood levels of the drug. The synthesis of such prodrugs and their evaluation in rodent models is reported.
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Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Tiamina
/
Transcetolasa
/
Profármacos
/
Inhibidores Enzimáticos
Idioma:
En
Revista:
Bioorg Med Chem Lett
Asunto de la revista:
BIOQUIMICA
/
QUIMICA
Año:
2008
Tipo del documento:
Article
País de afiliación:
Estados Unidos