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Benzimidazole derivatives as SIRTUIN modulators

A compound, R24 technology, applied in the direction of antitoxins, drug combinations, metabolic diseases, etc., can solve the problem of not prolonging 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

AI Technical Summary

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

[1670] Example 1 Synthesis and characterization of Sirtuin modulator

[1671] General route:

[1672] Route 1:

[1673]

[1674] Route 2:

[1675]

[1676] Route 3:

[1677]

[1678] Route 4:

[1679]

[1680] Test part:

[1681] Abbreviations used in the experimental part:

[1682] HATU=O-(7-azabenzotriazol-1-yl)-N,N,N’,N’-tetramethylurea hexafluorophosphate

[1683] NMM=4-Methylmorpholine

[1684] DIEA=N,N-diisopropylethylamine

[1685] DMF=N,N-Dimethylformamide

[1686] CH 2 Cl 2 = Dichloromethane

[1687] EtOAc = ethyl acetate

[1688] MeOH = methanol

[1689] Na 2 SO 4 = Sodium sulfate

[1690] PPA = polyphosphoric acid

[1691] Et 3 N = triethylamine

[1692] rt = room temperature

[1693] Preparation of 3-(thiazolo[5,4-c]pyridin-2-yl)aniline:

[1694]

[1695] 4-aminopyridin-3-yldiisopropylcarbamodithioate (4-aminopyridin-3-yldiisopropylcarbamodithioate) according to Smith et al, Sulfur Lett. 1994 vol 17, p.197 and E.Ma, Molecules 2003, vol 8, p.678-686.

[1696] ...

Embodiment 2

[2447] Example 2: Identification of Sirtuin modulators

[2448] An assay based on fluorescence polarization or mass spectrometry was used to identify the activity of SIRT1 modulators. 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 sirtuin deacetylation target-p53 fragment. Compounds 1-18 were detected with a substrate containing peptide 1 with the following 14 amino acid residues: GQSTSSHSK(Ac)NleSTEG (SEQ ID NO:1), where K(Ac) is an acetylated lysine residue, Nle It is norleucine. The peptide was labeled with the fluorescent group MR121 (excitation 635nm / emission 680nm) at the C-terminus, and biotin at the N-terminus. The sequence of the peptide substrate is based on a variety of modified p53. In particular, unlike acetylated lysine, all arginine and leucine residues are replaced by serine, making the peptide less prone to cleavage by trypsin in the absence of deac...

Embodiment 3

[2584] Example 3: Using SIRT3 to identify Sirtuin modulators

[2585] The activity of SIRT3 modulator was identified by fluorescence polarization assay. The same assay method can be used to identify any sirtuin protein modulator. This assay utilizes a peptide substrate based on the known sirtuin deacetylation target-histone H4 fragment. The substrate contains a peptide with the following 14 amino acid residues: Biotin-GASSHSK(Ac)VLK(MR121) (SEQ ID NO: 4), where K(Ac) is an acetylated lysine residue. The peptide was labeled with the fluorescent group MR121 (excitation 635nm / emission 680nm) at the C-terminus and biotin at the N-terminus.

[2586] Peptide substrate in NAD + Contact with sirtuin protein in the presence of deacetylation of the substrate makes it susceptible to trypsin-induced cleavage. Then trypsin is added and the reaction is completed (for example, the deacetylated substrate is cleaved), and the MR121 fragment is released. Then streptavidin is added to the reaction, ...

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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 for the following U.S. provisional applications: 60 / 705612 filed on August 4, 2005, 60 / 741783 filed on December 2, 2005, 60 / 779370 filed on March 3, 2006, and 2006 60 / 792276 filed on April 14th, the entire content of which is hereby incorporated as a reference. Background technique [0003] The Silent Information Regulator (SIR) family genes are highly conserved genes that exist in the genomes of organisms from archaea to various eukaryotes (Frye, 2000). Encoding the SIR protein involves a variety of processes from gene silencing to DNA repair. The proteins encoded by members of the SIR gene family show a high degree of sequence conservation in the core domain of 250 amino acids. The most characteristic gene in this family of genes is S. cerevisiae SIR2, which involves silent HM sites that contain information that determines the mating type, telomere position effect, and cellular senescence in yeast (Guarente, 199...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D471/04A61K31/435A61P3/00A61P25/00A61P27/00A61P39/00A61P7/00A61P21/00
Inventor J·J·努涅斯J·米尔恩J·S·迪施J·比米斯R·谢C·B·武P·Y·吴
Owner SIRTRIS PHARMA INC
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