Prodrug thiamine analogs as inhibitors of the enzyme transketolase
| Autor: | Allen A. Thomas, Todd Romoff, Laura Hayter, Jed Pheneger, Jason De Meese, Patrice Lee, Boyd Steven A, S. Kirk Wright, Christine Lemieux, Gunawardana Indrani W, Steven S. Gonzales, Walter E. DeWolf, Francis X. Sullivan, Yvan Le Huerou, Jie Lin, Gregory K. Poch, May Han, Tomas Kaplan, Solly Weiler |
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| Rok vydání: | 2008 |
| Předmět: |
chemistry.chemical_classification
Molecular Structure biology Chemistry Organic Chemistry Clinical Biochemistry Pharmaceutical Science Transketolase Pentose phosphate pathway Prodrug Biochemistry Cofactor Enzyme Pharmacokinetics Enzyme inhibitor Drug Discovery biology.protein Molecular Medicine Prodrugs Thiamine Enzyme Inhibitors Molecular Biology |
| Zdroj: | Bioorganic & Medicinal Chemistry Letters. 18:505-508 |
| ISSN: | 0960-894X |
| DOI: | 10.1016/j.bmcl.2007.11.100 |
| Popis: | 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: | OpenAIRE |
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