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US-20260124167-A1 - SIRTUIN ACTIVATOR OR EXPRESSION ENHANCER, NAD+ INCREASING AGENT, AND SENESCENT CELL INHIBITOR

US20260124167A1US 20260124167 A1US20260124167 A1US 20260124167A1US-20260124167-A1

Abstract

Provided is a novel use of a composition that contains a prescribed sulfur-containing compound, a salt thereof, or both. The present invention is a sirtuin activator or expression enhancer, a NAD+ increasing agent, or a senescent cell inhibitor containing, as an active ingredient, a compound (excluding S-1-propenylcysteine) represented by general formula 1A or 1B, or a salt thereof.

Inventors

  • Junichiro Suzuki
  • Masato Nakamoto

Assignees

  • WAKUNAGA PHARMACEUTICAL CO., LTD.

Dates

Publication Date
20260507
Application Date
20231012
Priority Date
20221012

Claims (6)

  1. 1 - 5 . (canceled)
  2. 6 . A method of increasing activation of, or enhancing expression of sirtuins, of increasing NAD + , or of suppressing senescent cells in an animal, the method comprising administering to the animal an effective amount of an agent comprising a compound represented by the following general formula 1A or 1B (excluding S-1-propenylcysteine) or a salt thereof: wherein R 1 represents an alkyl group that may have a substituent, an alkenyl group that may have a substituent, or an alkynyl group that may have a substituent, R 2 represents a hydrogen atom or an acyl group, R 3 represents a hydroxy group or a monosubstituted amino group, X represents a group represented by —S—, —S(O)—, —S(O) 2 —, —S—S—, —S—S—S—, or —S—S—S—S—, and n represents 1 or 2, and wherein Y represents a group represented by —S— or —S(O)—.
  3. 7 . The method of claim 6 , wherein in the general formula 1A, R 1 represents a C1 to C8 alkyl group that may have a substituent, a C2 to C8 alkenyl group that may have a substituent, or a C2 to C8 alkynyl group that may have a substituent, R 2 represents a hydrogen atom, a C1 to C3 alkylcarbonyl group, or a residue obtained by removing-OH from a carboxy group of an amino acid, and R 3 represents a hydroxy group or a residue obtained by removing one hydrogen atom from an amino group of an amino acid.
  4. 8 . The method of claim 7 , wherein in the general formula 1A, R 1 represents a C1 to C8 alkyl group, a hydroxy C1 to C8 alkyl group, a C2 to C8 alkenyl group, or a C2 to C8 alkynyl group, R 2 represents a hydrogen atom, R 3 represents a hydroxy group, and X represents a group represented by —S—, —S(O)— or —S—S—.
  5. 9 . The method of claim 6 , wherein in the formula 1B, Y represents a group represented by —S—.
  6. 10 . The method of claim 6 , wherein the compound is a compound represented by any of the following structural formulae.

Description

TECHNICAL FIELD The present invention relates to an agent for use in activation or expression enhancement of a sirtuin, NAD+ increase, and senescent cell suppression. BACKGROUND ART Sirtuins are known as molecules, for example, in nematodes, flies, and mammals, whose high expression can prolong lifespan while deficiency thereof can shorten such lifespan. Genes of sirtuins that are NAD+ dependent deacetylases are widely conserved from bacteria to eukaryotes. Sirtuins have been attracting attention as candidates for longevity genes in animals, because deficiency of Sir2, which is a sirtuin homolog of yeast and nematodes, shortens the lifespan, while overexpression of Sir2 prolongs the lifespan. There are seven sirtuins (SIRT1 to SIRT7) in mammals, and among them, SIRT1 having a structure and function that is the most similar to yeast Sir2 has been revealed to be probably involved in controlling a wide range of cellular functions such as gene expression associated with aging, intracellular metabolism, energy consumption, inflammation, and stress response pathways (Non-Patent Literature 1). In recent years, it has been revealed that sirtuins may be related to specific diseases. For example, Non-Patent Literature 2 shows that cognitive functions including immediate memory, classical conditioning, and spatial learning are impaired in SIRT1 knockout mice. Conversely, overexpression of SIRT1 is observed to exhibit ordered synaptic plasticity and memory. It has been revealed that SIRT1 acts on normal learning, memory, and synaptic plasticity. Furthermore, Non-Patent Documents 3 and 4 describe relationships of SIRT1 with liver steatosis and cardiac function respectively. Nicotinamide mononucleotide (NAD+) functions as a coenzyme for dehydrogenases and a substrate for sirtuins in living bodies. It is also known that an increase in NAD+ amount enhances sirtuins activity. Synthesis of NAD is controlled by nicotinamide phosphoribosyltransferase (NAMPT). It is known that decreased function of NAMPT with age leads to reduced NAD+ amount and decreased sirtuins activity. Non-Patent Document 5 discloses that administration of nicotinamide riboside, which is a precursor of NAD+, suppresses cellular senescence in brain. Non-Patent Documents 6 and 7 describe relationships of NAD+ with nonalcoholic fatty liver diseases and kidney injuries respectively. Cellular senescence is a phenomenon of the occurrence of irreversible cell cycle arrest that results from excessive DNA damage via accumulation of DNA replication errors associated with cell division, oxidative stress, radiation, activation of oncogenes, or the like, which activates p16/RB pathways and p53/p21 pathways, inducing inhibitors of cyclin inhibitor kinase. Cells that have undergone the cellular senescence (the senescent cells) accumulate in tissues due to accelerated cellular senescence and reduced removal ability caused by decline in mitochondria and immune functions associated with aging. The senescent cells accumulated in tissues secrete, for example, inflammatory cytokines, proteases, etc., which are called cellular senescence associated secretory factors, thereby damaging surrounding tissues and accelerating aging of tissues and living bodies. On the other hand, it has been suggested that removal of senescent cells may prevent or delay tissue dysfunction to suppress the senescence (Non-Patent Document 8). Furthermore, it has been revealed that an increase in senescent cells is involved in kidney injuries (Non-Patent Document 9) and fatty liver (Non-Patent Document 10). On the other hand, it is known that sulfur-containing components present in natural plants of the genus Arium, particularly garlic, etc. can have various biological functions. Examples of such components include S-alkyl(alkenyl)mercaptocysteine (Non-Patent Document 11), S-methylcysteine sulfoxide (Non-Patent Document 12), and S-allylcysteine sulfoxide (Non-Patent Document 13). However, sirtuin activation, senescent cell suppression, and NAD+ increase by known sulfur-containing components are not known at all. CITATION LIST Non-Patent Document Non-Patent Document 1: Trends Cell Biol. 2014; 24 (8): pp. 464-71Non-Patent Document 2: J Neurosci 2010; 30 (29): pp. 9695-9707Non-Patent Document 3: Molecular Medicine Reports 2018; 18: pp. 1609-1615Non-Patent Document 4: Aging 2021; 13 (10): pp. 14482-14498Non-Patent Document 5: Cell Metab. 2018 Mar. 6; 27 (3): pp. 513-528Non-Patent Document 6: British Journal of Pharmacology 2016; 173: pp. 2352-2368Non-Patent Document 7: Nature 2016; 531 (7595): pp. 528-532Non-Patent Document 8: Nature. 2011 Nov. 2; 479 (7372): pp. 232-6Non-Patent Document 9: Front Pharmacol. 2019; 10: 770Non-Patent Document 10: Nature Communications 2017; 8: 15691Non-Patent Document 11: J. Agric. Food Chem. 2013; 61: pp. 1896-1903Non-Patent Document 12: Tissue Cell 2021; 69: 101483Non-Patent Document 13: International Journal of Molecular Medicine 2019; 44: pp. 1943-1951 DISCLOSURE OF THE INV