Thiazolopyridine sirtuin modulating compounds

A technology of compounds and compositions, applied in the compound field of thiazolopyridine sirtuin regulators, capable of solving problems such as prolonging the lifespan of wild-type cells and reducing

Inactive Publication Date: 2012-03-21
SIRTRIS PHARMA INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Furthermore, mutations that reduce the activity of the yeast glucose-responsive cAMP (adenosine 3′,5′-monophosphate)-dependent (PKA) pathway extend lifespan in wild-type cells but not in mutant sir2 strains extension, which demonstrates that SIR2 may be a key downstream component of the caloric restriction pathway

Method used

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  • Thiazolopyridine sirtuin modulating compounds
  • Thiazolopyridine sirtuin modulating compounds
  • Thiazolopyridine sirtuin modulating compounds

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0286] Example 1. Preparation of sirtuin-modulating compounds and precursors thereof

[0287] Preparation of 2-(thiazolo[5,4-b]pyridin-2-yl)aniline:

[0288]

[0289] A mixture of 3-amino-2-chloropyridine (3.85g, 29.95mmol) and 2-nitrobenzoyl chloride (5.56g, 29.95mmol) in pyridine (50mL) was stirred at 0°C for 1 hour, then at room temperature Stir overnight. Water was added and the formed precipitate was collected by filtration and dried to give N-(2-chloropyridin-3-yl)-2-nitrobenzamide as a white solid (8.52 g, crude yield: >100%) .

[0290] N-(2-chloropyridin-3-yl)-2-nitrobenzamide (12.98g, 46.75mmol), P 2 S 5(31.17 g, 140.24 mmol) and pyridine (80 mL) in p-xylene (310 mL) was heated at 120° C. for 18 hours. Stirring was stopped for 30 min and the mixture was cooled to 100 °C. The upper clear solution was transferred and concentrated in vacuo, followed by the addition of ethanol (50 mL). The suspension was heated at 75°C for 30 minutes to dissolve the product, fi...

Embodiment 2

[0447] Example 2. Biological activity

[0448] Modulators of SIRT1 activity were identified using mass spectrometry-based assays. This mass spectrometry-based assay utilizes the following peptide of 20 amino acid residues: Ac-EE-K(biotin)-GQSTSSHSK(Ac)NleSTEG-K(5TMR)-EE-NH2 (SEQ ID NO: 1), Where K(Ac) is an acetylated lysine residue, and Nle is norleucine. The peptide was C-terminally labeled with the fluorophore 5TMR (excitation 540nm / emission 580nm). The sequence of this peptide substrate is based on p53 with several modifications. In addition, the methionine residue naturally occurring in this sequence was replaced with norleucine, since methionine may be easily oxidized during synthesis and purification.

[0449] Mass spectrometry was performed as follows: 0.5 μM peptide substrate and 120 μM βNAD + With 10nM SIRT1 at 25°C in reaction buffer (50mM Tris-acetate pH 8, 137mM NaCl, 2.7mM KCl, 1mM MgCl 2 , 5mM DTT, 0.05% BSA) for 25 minutes. Test compounds can be added t...

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PUM

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Abstract

Provided herein are novel sirtuin-modulating compounds of Structural Formula (Ia) and methods of use thereof. The sirtuin-modulating compounds may be used for increasing the lifespan of a cell, and treating and / or preventing a wide variety of diseases and disorders including, for example, diseases or disorders related to aging or stress, diabetes, obesity, neurodegenerative diseases, cardiovascular disease, blood clotting disorders, inflammation, cancer, and / or flushing as well as diseases or disorders that would benefit from increased mitochondrial activity. Also provided are compositions comprising a sirtuin-modulating compound in combination with another therapeutic agent.

Description

[0001] References to related applications [0002] This application claims the benefit of US Provisional Application No. 61 / 203,156, filed December 19, 2008, the contents of which are incorporated herein by reference. Background technique [0003] The Silent Information Regulator (SIR) family of genes represents a highly conserved group of genes present in the genomes of organisms ranging from archaebacteria to higher eukaryotes. The encoded SIR proteins are involved in various programs ranging from the regulation of gene silencing to DNA repair. Proteins encoded by members of the SIR gene family show a high degree of sequence conservation in the 250 amino acid core domain. A well-characterized gene in this family is S. cerevisiae SIR2, which involves a silent HM locus containing information specifying yeast mating type, telomere position effects, and cellular aging. The yeast Sir2 protein belongs to the family of histone deacetylases. The Sir2 homologue (CobB), in Salmonel...

Claims

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Application Information

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IPC IPC(8): C07D513/04A61P3/00A61P25/00A61K31/437A61P5/50A61P31/00A61K31/496A61P9/00A61P37/00A61K31/5377A61P19/00
CPCA61K31/5377A61K31/496A61K31/437A61K45/06C07D513/04A61P19/00A61P25/00A61P3/00A61P3/04A61P31/00A61P37/00A61P43/00A61P5/50A61P9/00A61P3/10A61K31/429
Inventor C·奥尔曼J·S·迪施P·Y·恩格R·B·珀尼
Owner SIRTRIS PHARMA INC
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