Discovery of Imidazo[1,2-b]thiazole Derivatives as Novel SIRT1 Activators
| Autor: | Philip D. Lambert, David J. Gagne, Joseph J. Nunes, Jerrold M. Olefsky, Jean Bemis, Chi B. Vu, Jill C. Milne, Amy V. Lynch, J. Joshua Smith, David P. Carney, Michael R. Jirousek, Robert B. Perni, Pui Yee Ng, Jeremy S. Disch, Simon Schenk, Siva Lavu |
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| Rok vydání: | 2009 |
| Předmět: |
medicine.drug_class
Stereochemistry Enzyme Activators Carboxamide Chemical synthesis Diabetes Mellitus Experimental Mice Structure-Activity Relationship Enzyme activator chemistry.chemical_compound Sirtuin 1 Quinoxalines Amide Drug Discovery medicine Animals Hypoglycemic Agents Structure–activity relationship Thiazole Bicyclic molecule Imidazoles Rats Rats Zucker Thiazoles Diabetes Mellitus Type 2 chemistry Molecular Medicine NAD+ kinase |
| Zdroj: | Journal of Medicinal Chemistry. 52:1275-1283 |
| ISSN: | 1520-4804 0022-2623 |
| Popis: | A series of imidazo[1,2-b]thiazole derivatives is shown to activate the NAD(+)-dependent deacetylase SIRT1, a potential new therapeutic target to treat various metabolic disorders. This series of compounds was derived from a high throughput screening hit bearing an oxazolopyridine core. Water-solubilizing groups could be installed conveniently at either the C-2 or C-3 position of the imidazo[1,2-b]thiazole ring. The SIRT1 enzyme activity could be adjusted by modifying the amide portion of these imidazo[1,2-b]thiazole derivatives. The most potent analogue within this series, namely, compound 29, has demonstrated oral antidiabetic activity in the ob/ob mouse model, the diet-induced obesity (DIO) mouse model, and the Zucker fa/fa rat model. |
| Databáze: | OpenAIRE |
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