Discovery of Imidazo[1,2-b]thiazole Derivatives as Novel SIRT1 Activators

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• 作者：Chi B. Vu* ; Jean E. Bemis ; Jeremy S. Disch ; Pui Yee Ng ; Joseph J. Nunes ; Jill C. Milne ; David P. Carney ; Amy V. Lynch ; Jesse J. Smith ; Siva Lavu ; Philip D. Lambert ; David J. Gagne ; Michael R. Jirousek
• 刊名：Journal of Medicinal Chemistry
• 出版年：2009
• 出版时间：March 12, 2009
• 年：2009
• 卷：52
• 期：5
• 页码：1275-1283
• 全文大小：240K
• 年卷期：v.52,no.5(March 12, 2009)
• ISSN：1520-4804

文摘

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.