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Benzimidazole derivatives as SIRTUIN modulators

A phenyl and compound technology, applied in the field of benzimidazole derivatives as SIRTUIN regulators, can solve problems such as the inability to prolong the lifespan of mutant sir2 strains

Inactive Publication Date: 2008-10-08
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 prolong lifespan in wild-type cells but not in mutant sir2 strains, suggesting that SIR2 has Possibly a key component in the downstream region of the caloric restriction pathway (Lin et al., 2001)

Method used

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  • Benzimidazole derivatives as SIRTUIN modulators
  • Benzimidazole derivatives as SIRTUIN modulators
  • Benzimidazole derivatives as SIRTUIN modulators

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[1691] Synthesis and characterization of embodiment 1 Sirtuin modulator

[1692] General route:

[1693] Route 1:

[1694]

[1695] Route 2:

[1696]

[1697] Route 3:

[1698]

[1699] Route 4:

[1700]

[1701] Experimental part:

[1702] Abbreviations used in the experimental part:

[1703] HATU=O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate

[1704] NMM=4-methylmorpholine

[1705] DIEA=N,N-Diisopropylethylamine

[1706] DMF=N,N-Dimethylformamide

[1707] CH 2 Cl 2 = dichloromethane

[1708] EtOAc = ethyl acetate

[1709] MeOH = Methanol

[1710] Na 2 SO 4 = sodium sulfate

[1711] PPA = polyphosphoric acid

[1712] Et 3 N = triethylamine

[1713] rt = room temperature

[1714] Preparation of 3-(thiazolo[5,4-c]pyridin-2-yl)aniline:

[1715]

[1716] 4-aminopyridin-3-yldiisopropylcarbamoylcarbamodithioate (4-aminopyridin-3-yldiisopropylcarbamodthioate) according to Smith et al, Sulfur Lett.1994 vol 17, p.197 an...

Embodiment 2

[2459] Example 2: Identification of Sirtuin Modulators

[2460] The activity of SIRT1 modulators is identified using fluorescence polarization or mass spectrometry based assays. The same assay can be used to identify modulators of any sirtuin protein. The fluorescence polarization assay uses one of two different peptides based on the known target of sirtuin deacetylation - the p53 fragment. Compounds 1-18 were detected with a substrate containing peptide 1 having the following 14 amino acid residues: GQSTSSHSK(Ac)NleSTEG (SEQ ID NO: 1), where K(Ac) is an acetylated lysine residue, Nle For norleucine. The peptide was labeled C-terminally with the fluorophore MR121 (excitation 635 nm / emission 680 nm) and N-terminally with biotin. The sequences of the peptide substrates are based on p53 with various modifications. In particular, unlike acetylated lysines, all arginine and leucine residues are replaced with serines, rendering the peptide less susceptible to cleavage by trypsin...

Embodiment 3

[2596] Example 3: Identification of Sirtuin Modulators Using SIRT3

[2597] Identification of SIRT3 modulator activity by fluorescence polarization assay. Any modulator of a sirtuin protein can be identified using the same assay. The assay utilizes a peptide substrate based on a known sirtuin deacetylation target, the histone H4 fragment. The substrate contained a peptide with the following 14 amino acid residues: Biotin-GASSSHSK(Ac)VLK(MR121) (SEQ ID NO: 4), where K(Ac) is an acetylated lysine residue. The peptide was labeled C-terminally with the fluorophore MR121 (excitation 635 nm / emission 680 nm) and N-terminally with biotin.

[2598] Peptide substrates in NAD + Exposure to the presence of sirtuin proteins deacetylates the substrate, rendering it susceptible to cleavage by trypsin. Then trypsin was added, and the reaction was carried out to completion (eg, the deacetylated substrate was cleaved), releasing the MR121 fragment. Streptavidin, which binds the uncleaved s...

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Abstract

Provided herein are novel sirtuin-modulating compounds and methods of use thereof. The sirtuin-modulating compounds may be used for increasing the lifespan of a cell, and treatin 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 benfit from increased mitochondrial activity. Also provided are compositions comprising a sirtuin-modulating compound in combination with another therapeutic agent.

Description

[0001] related application [0002] This application claims priority to the following U.S. provisional applications: 60 / 705612 filed August 4, 2005, 60 / 741783 filed December 2, 2005, 60 / 779370 filed March 3, 2006, and 2006 60 / 792276, filed April 14, which is hereby incorporated by reference in its entirety. Background technique [0003] The silent information regulator (SIR) family of genes are highly conserved genes present in the genomes of organisms ranging from archaea to various eukaryotes (Frye, 2000). The encoded SIR proteins are involved in a variety of processes ranging from the regulation of gene silencing to DNA repair. The proteins encoded by members of the SIR gene family show high 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 determining yeast mating type, telomere position effects, and cellular senescence (Guarente, 1999; Kaeberlei...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61P3/00A61P7/00A61P21/00A61P25/00A61P27/00A61P35/00A61K31/435A61K31/495A61K31/41C07D235/18C07D401/12C07D403/12
Inventor J・J・努涅斯J・米尔恩J・比米斯R・谢C・B・武P・Y・吴J・S・迪施
Owner SIRTRIS PHARMA INC
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