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Acss2 inhibitors and methods of use thereof

A CF3, C1-C5 technology, applied in the field of novel ACSS2 inhibitors, can solve problems such as targetable metabolic fragility

Pending Publication Date: 2020-08-21
美特波米德有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

These observations may make ACSS2 a targetable metabolic vulnerability in a broad variety of tumors

Method used

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  • Acss2 inhibitors and methods of use thereof
  • Acss2 inhibitors and methods of use thereof
  • Acss2 inhibitors and methods of use thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0444] The synthetic detail of compound of the present invention ( Figure 1-3 )

[0445] Experimental steps:

[0446] General Synthesis of Compound 3

[0447]

[0448] in N 2 A solution of Compound 1 (1.00 equiv), Compound 2 (1.0 equiv) in AcOH (0.5 to 10 mL) was stirred at 90°C for 3 to 10 hours. The mixture was concentrated in vacuo. The residue was purified by trituration (in ethyl acetate or EtOH) to afford compound 3.

[0449] General Preparation of Compound 5

[0450]

[0451] To a solution of compound 3 (1.00 equiv) in DCM (5 to 10 mL) was added Et 3 N (2.00 equiv). After stirring at 25 °C for 30 minutes, compound 4 (1.00 equiv) was added, and then 2 The mixture was stirred at 25°C for 2.5 hours. It was concentrated in vacuo to afford crude compound 5, which was used as such in the next step.

[0452] General Preparation of Final Compound 100-277

[0453] method 1

[0454]

[0455] To a solution of compound 5 (1.50 equiv) in MeCN (10 mL), HOBT (2.0...

Embodiment 2

[0998] Biological Activity of Compounds of the Invention

[0999] ACSS2 cell-free viability assay (cell-free IC 50 )

[1000] The assay is based on a coupled reaction with pyrophosphatase: ACSS2 is converting ATP+CoA+acetate => AMP+pyrophosphate+acetyl-CoA (Ac-CoA). Pyrophosphatase converts pyrophosphate, the product of the ACSS2 reaction, into phosphate, which can be detected by measuring absorbance at 620 nm after incubation with Biomol green reagent (Enzo life Science, BML-AK111).

[1001] cell-free IC 50 Determination:

[1002] 10 nM human ACSS2 protein (OriGene Technologies, Inc) was incubated at 37° C. for 90 minutes at various compound concentrations in reactions containing 50 mM Hepes pH 7.5, 10 mM DTT, 90mM KCl, 0.006% Tween-20, 0.1mg / ml BSA, 2mM MgCl 2 , 10 μM Coenzyme A, 5 mM NaAc, 300 μM ATP and 0.5 U / ml pyrophosphatase (Sigma). At the end of the reaction, Biomol Green was added for 30 minutes at room temperature, and the activity was measured by reading the ...

Embodiment 3

[1033] In Vivo Efficacy of Compound 265 in MDA-MB-468 Breast Cancer Cell Xenografts

[1034] In vivo efficacy studies were performed by Charles-River Laboratories, Freiburg, Germany site.

[1035] Tumor masses from the breast cancer cell line MDA-MB-468, passaged as subcutaneous xenografts, were implanted subcutaneously into female NMRI nude mice (Crl:NMRI-Foxn1nu). When the tumor volume reaches 50 to 250mm 3 , the animals were randomly grouped. Vehicle control or Compound 265 was dosed orally at 100 mg / kg once daily. Body weight and tumor volume [mm3] were measured by calipers twice a week.

[1036] The results showed that in the group treated with 100mg / kg compound 265, the growth of the tumor was significantly delayed ( Figure 4 ).

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Abstract

The present invention relates to novel ACSS2 inhibitors having activity as anti-cancer therapy, treatment of alcoholism, and viral infection (e.g., CMV), composition and methods of preparation thereof, and uses thereof for treating viral infection, alcoholism, alcoholic steatohepatitis (ASH), non-alcoholic steatohepatitis (NASH), obesity / weight gain, anxiety, depression, post-traumatic stress disorder, inflammatory / autoimmune conditions and cancer, including metastatic cancer, advanced cancer, and drug resistant cancer of various types.

Description

technical field [0001] The present invention relates to novel ACSS2 inhibitors, compositions and methods for their preparation and use thereof for the treatment of viral infections (eg CMV), alcoholism, alcoholic steatohepatitis (ASH), non-alcoholic steatohepatitis (NASH) , metabolic disorders (including: obesity, weight gain, and hepatic steatosis), neuropsychiatric disorders (including: anxiety, depression, schizophrenia, autism, and post-traumatic stress disorder), inflammatory / autoimmune sexual conditions and cancers (including all types of metastatic cancers, advanced cancers, and drug-resistant cancers). Background technique [0002] Cancer is the second most common cause of death in the United States, after heart disease. Cancer accounts for 1 in 4 deaths in the United States. The 5-year relative survival rate for all cancer patients diagnosed in 1996-2003 was 66%, up from 50% in 1975-1977 (Cancer Facts & Figures, American Cancer Society: Atlanta, GA (2008 year)). ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D231/08C07D401/12C07D403/12C07D405/12C07D409/12C07D413/12A61K31/4152A61K31/4155A61P35/00A61P3/00A61P25/00A61P29/00A61P31/12A61P37/02
CPCC07D403/12C07D401/14C07D405/14C07D413/14A61K31/4152A61K31/4155C07D231/20C07D231/22C07D231/26C07D401/04C07D401/10C07D401/12C07D403/04C07D403/10C07D405/04C07D405/10C07D405/12C07D409/04C07D409/12C07D413/10C07D413/12C07D417/12A61P37/02A61P25/00A61P3/00A61P29/00A61P35/00A61P31/12C07F5/025A61K45/06A61K31/69A61K31/4178A61K31/497A61K31/454A61K31/422A61K31/4439A61K31/506A61K31/4196A61K31/427A61K31/4184A61K31/4709A61K2300/00
Inventor P·纳卡什O·埃雷兹S·博蒂A·哥特普洛斯M·拉贝尔
Owner 美特波米德有限公司
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