| Autor: |
Le Huerou Y; Array BioPharma Inc., 3200 Walnut Street, Boulder, CO 80301, USA. yhuerou@arraybiopharma.com, Gunawardana I, Thomas AA, Boyd SA, de Meese J, Dewolf W, Gonzales SS, Han M, Hayter L, Kaplan T, Lemieux C, Lee P, Pheneger J, Poch G, Romoff TT, Sullivan F, Weiler S, Wright SK, Lin J |
| Jazyk: |
angličtina |
| Zdroj: |
Bioorganic & medicinal chemistry letters [Bioorg Med Chem Lett] 2008 Jan 15; Vol. 18 (2), pp. 505-8. Date of Electronic Publication: 2007 Dec 03. |
| DOI: |
10.1016/j.bmcl.2007.11.100 |
| Abstrakt: |
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. |
| Databáze: |
MEDLINE |
| Externí odkaz: |
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