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Senolytic compounds

A technology for senescent cells and compounds, applied in the field of senescent cell clearance compounds and compounds for the treatment of aging-related diseases or conditions, which can solve problems such as thrombocytopenia, low solubility and oral bioavailability

Pending Publication Date: 2020-01-10
英国研究与创新公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

ABT-737 is a small molecule inhibitor of BCL-2, BCL-XL and BCL-W, but has low solubility and oral bioavailability
ABT-263 inhibits the same molecule and is more suitable for in vivo application, but the side effect of ABT-263 is to cause significant thrombocytopenia

Method used

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Embodiment

[0256] Materials and methods

[0257] The agents described herein are commercially available agents. For example, the following compounds were obtained from the Library of Pharmacologically Active Compounds (LOPAC; SigmaAldrich):

[0258] PF-573228

[0259] JFD00244

[0260] Oabainin

[0261] Bufalin

[0262] elatoside K

[0263] Toxinangenin

[0264] Digoxin

[0265] Cyclosporine

[0266] Tyrosine phosphorylation inhibitor AG879

[0267] Cantharidin

[0268] Diphenylene iodonium chloride (DPI)

[0269] Fusaicin

[0270] 2,3-Dimethoxy-1,4-naphthoquinone

[0271] LY-367,265

[0272] Rotenone

[0273] idabi star

[0274] Dequalinium chloride

[0275] vincristine

[0276] The following compounds were obtained from the Selleck chemical library:

[0277] Atorvastatin Calcium (Lipitor),

[0278] fluvastatin sodium (Lescol)

[0279] Lovastatin (Mevacor)

[0280] pitavastatin calcium (Livalo)

[0281] Simvastatin (Zocor)

[0282] Nitazoxanide (Alinia, Annita)

...

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Abstract

The present invention relates to an agent for use in selectively killing one or more senescent cells, wherein the agent is selected from the following: a cardiac glycoside or alglycone, a focal adhesion kinase (FAK) inhibitor, an HMG-CoA reductase inhibitor, JFD00244, Cyclosporine, Tyrphostin AG879, Cantharidin, Diphenyleneiodonium chloride, Rottlerin, 2,3-Dimethoxy-1,4-naphthoquinone, LY-367,265,Rotenone, Idarubicin, Dequalintum chloride, Vincristine, Nitazoxanide, Nitrofurazone, Temsirolimus, Eltrombopag, Adapalene, Azacyclonol, Enoxacin and Raltegravir, and pharmaceutically acceptable salts thereof. Another aspect relates to compounds for use in treating or preventing a senescence- associated disease or disorder, and methods relating thereto.

Description

technical field [0001] The present invention relates to compounds capable of selectively killing senescent cells without killing non-senescent cells, ie, senolytic compounds. The present invention also provides compounds for use in the treatment of diseases or conditions associated with aging, and methods related to the compounds. Background technique [0002] Senescence is a cellular program that forces damaged or old cells into a steady stasis to avoid their replication. In addition to growth arrest, senescent cells undergo profound phenotypic changes, including chromatin reorganization, increased β-galactosidase activity (termed senescence-associated β-galactosidase or SA-β-Gal), and multiple factors (mainly pro-inflammatory cytokines), collectively referred to as the senescence-associated secretory phenotype (SASP). [0003] Replicative senescence is activated upon successive passages of cells in culture (or as cells age in an organism). Senescence can also be induced...

Claims

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Application Information

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IPC IPC(8): A61K31/704A61K31/585A61P43/00
CPCA61K31/585A61K31/704A61P43/00A61K31/03A61K31/122A61K31/137A61K31/18A61K31/34A61K31/352A61K31/426A61K31/4709A61K31/4745A61K31/475A61K38/13A61K45/06
Inventor 耶稣·吉尔安娜·格雷罗尼古拉斯·哈兰兹
Owner 英国研究与创新公司
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