Discovery of Imidazo[1,2-b]thiazole Derivatives as Novel SIRT1 Activators 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, Simon Schenk, † Jerrold M. Olefsky, † and Robert B. Perni Sirtris Pharmaceuticals, 200 Technology Square, Cambridge, Massachusetts 02139 ReceiVed September 5, 2008 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. Introduction There are seven known sirtuin members (SIRT1-SIRT7) in the histone deacetylase (HDAC a ) family commonly referred to as class III HDACs, and SIRT1 is the most characterized member of the family. Unlike classes I and II HDACs, SIRT1 and other class III HDACs utilize nicotinamide adenine di- nucleotide (NAD + ) to catalyze protein deacetylation to afford nicotinamide and O-acetyl-ADP-ribose. Early studies have established an important link between SIRT1 and a number of metabolic functions that could possibly influence lifespan in lower organisms and rodents. 1 Two of the known consequences of SIRT1 activation are up-regulation of PGC-1R and increase in mitochondrial biogenesis, 2 both of which are beneficial biologic responses that are similarly induced by calorie restriction. 3,4 Since an increase in mitochondrial biogenesis could lead to improved glucose metabolism in various skeletal, muscle, and adipose tissues, activation of SIRT1 could potentially serve as a novel approach to treat type II diabetes and other metabolic disorders. 5 Recent work has shown that transgenic mice overexpressing SIRT1 are leaner than their control littermates and display a significantly improved metabolic profile such as lower levels of blood cholesterol, adipokines, insulin, and fasted blood glucose. 6 Resveratrol, a small molecule activator of SIRT1, has been reported to extend lifespan in yeast, 7 C. elegans, Drosophila, 8 and rodents. 9 In rodents, resveratrol, when dosed at 400 mg/kg over a period of 15 weeks, improves metabolism, glucose tolerance, and their overall physical performance in response to a rotarod or string test. 2 Since resveratrol has been shown to activate SIRT1 only at high doses, because of its lower potency, there was an immediate need to identify potent and selective compounds for proof-of-concept studies. Recent high throughput screening efforts to find novel SIRT1 activators from our laboratories have resulted in the discovery of the oxazolopyridine derivative 1 (Figure 1), a significant new chemical entity that is structurally distinct from resveratrol. 10 Discussion In order to assess SIRT1 activation, a high throughput mass spectrometry enzymatic assay was used. Potency was displayed as the EC 1.5 , the concentration of compound required to increase enzyme activity by 50%, and the percent maximum activation that could be achieved at the highest doses of the compound being tested. In this type of assay, resveratrol has an EC 1.5 value of 48 µM and a 250% maximum activation whereas the oxazolopyridine derivative 1 has a corresponding EC 1.5 value of 11 µM and a 388% maximum activation. Preliminary work has already shown that the potency of this lead could be improved to a level that has not been observed before with resveratrol. 10 We have since modified the oxazolopyridine moiety with a novel imidazo[1,2-b]thiazole ring and have noted a similar level of SIRT1 activation (2, EC 1.5 ) 7.5 µM, 380% maximum activation). When an ortho substitution pattern was adopted at the middle phenyl ring, an increase in potency was observed (3, EC 1.5 ) 2.5 µM, 272% maximum activation). The imidazo[1,2-b]thiazole ring offers the opportunity to install a variety of functional groups, such as amino derivatives, conveniently at either the C-2 or C-3 position of the molecule. As shown in Scheme 1, when ethyl 2-aminothiazole-4-carboxy- * To whom correspondence should be addressed. Phone: (617)-252-6920, extension 2129. Fax: (617)-252-6924. E-mail: cvu@sirtrispharma.com. † Present address: Department of Medicine, Division of Endocrinology and Metabolism, University of CaliforniasSan Diego, 9500 Gilman Drive, La Jolla, CA 92093. a Abbreviations: HDAC, histone deacetylase; NAD + , nicotinamide adenine dinucleotide; PGC-1R, peroxisome proliferator-activated receptor coactivator-1R; DIO, diet-induced obesity. Figure 1 J. Med. Chem. 2009, 52, 1275–1283 1275 10.1021/jm8012954 CCC: $40.75  2009 American Chemical Society Published on Web 02/06/2009