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Heterocyclic modulators of lipid synthesis

A compound, cycloalkyl technology, applied in plant growth regulators, peptide/protein components, active ingredients of heterocyclic compounds, etc., can solve the problems of anemia, weakened nutrient absorption, impaired immune function, destruction, etc. Viral and anticancer therapy, effects of improved antiviral and anticancer activity

Active Publication Date: 2014-02-05
GANNEX PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Both radiation-based and cytotoxic-based therapies cause damage to rapidly dividing hematopoietic and intestinal epithelial cells, resulting in impaired immune function, anemia, and reduced nutrient absorption

Method used

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  • Heterocyclic modulators of lipid synthesis
  • Heterocyclic modulators of lipid synthesis
  • Heterocyclic modulators of lipid synthesis

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[2528] Example 1 - FASN Inhibition by Compounds of the Disclosure

[2529] Determination of FASN biochemical activity: FASN enzyme was isolated from SKBr3 cells. SKBr3 is a human breast cancer cell line with high expression levels of FASN. FASN is expected to comprise about 25% of the cytosolic protein in this cell line. SKBr3 cells were homogenized in a dounce homogenizer, followed by centrifugation at 4°C for 15 minutes to remove particulate matter. Supernatants were then analyzed for protein content, diluted to appropriate concentrations and used to measure FASN activity. The presence of FASN was confirmed by immunoblot analysis. A similar method for isolation of FASN from SKBr3 cells is described in Teresa, P. et al. (Clin. Cancer Res. 2009; 15(24), 7608-7615).

[2530] FASN activity of SKBr3 cell extracts was determined by measuring NADPH oxidation or the amount of thiol-containing coenzyme A (CoA) released during fatty acid synthase reactions. The dye CPM (7-dieth...

Embodiment 2

[2531] Example 2 - Antiviral Activity

[2532] The antiviral activity of constructs (I-Z) was assessed using the HCV 1b replicon system:

[2533]

[2534] The replicon was constructed using the ET (luc-ubi-neo / ET) cell line, which is an HCV replicon with a stable luciferase (Luc) reporter and Three cell culture-adaptive mutant Huh7 human hepatoma cell lines (Pietschmann et al. (2002) J. Virol. 76:4008-4021). The HCV Replicon Antiviral Evaluation Assay investigated the effect of compounds at six half-log concentrations. Human interferon alpha-2b was included in each run as a positive control compound. Sub-confluent cultures of the ET line were plated out in 96-well plates dedicated to analysis of cell number (cytotoxicity) or antiviral activity and drugs were added to the appropriate wells the next day. Cells were processed 72 hours later when they were still near confluence. Determination of EC 50 (The replicon was inhibited by 50% and 90% respectively), IC 50 (conc...

Embodiment 3

[2537] Example 3 - FASN Inhibition Correlates with HCV Inhibition

[2538] The antiviral activity of 15 compounds of the disclosure was measured using the HCV replicon system (numbers correlate to compounds in Table 1). According to published methods (Lohmann et al., (1999) Science 285(5424): 110-113; Lohmann et al., (2001) J.Virol75(3): 1437-1449 and Qi et al., (2009) Antiviral Res. 81(2):166-173), Huh7 was used to establish the replicon cell line 1b (HCV 1b / Luc-Neo replicon (1b Con1 integrated with firefly gene)) by G418 selection. Replicon assembly using synthetic gene fragments. The GT1b line has PV-EKT and has 3 adaptive mutations E1202G (NS3), T1280I (NS3), K1846T (NS4B) and the backbone is Con1. The medium is:

[2539] a) DMEM supplemented with 10% FBS, G418 (250 μg / ml), streptomycin (100 μg / ml) / penicillin (100U / ml), L-glutamine (100×), NEAA (100×)

[2540] b) The culture medium is prepared as follows:

[2541] i) 500ml DMEM medium (Gibco, catalog number 11960-07...

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Abstract

Compounds that are fatty acid synthesis modulators are provided. The compounds may be used to treat disorders characterized by disregulation of the fatty acid synthase function by modulating the function and / or the fatty acid synthase pathway. Methods are provided for treating such disorders including viral infections, such as hepatits C infection, cancer and metabolic disorders.

Description

[0001] related application [0002] This application claims U.S. Application No. 61 / 450,561, filed March 8, 2011, U.S. Application No. 61 / 508,611, filed July 16, 2011, and U.S. Application 61 / 585,642, each of which is incorporated herein by reference in its entirety for all purposes. field of invention [0003] The present disclosure generally relates to heterocyclic modulators of lipid synthesis and methods of their use. Heterocyclic modulators of lipid synthesis of the present disclosure are useful for treating disorders characterized by dysfunctional fatty acid synthase in an individual by modulating the fatty acid synthase pathway and / or fatty acid synthase function. Background of the invention [0004] Viral diseases are major health problems that threaten most of the human population. Some of the characteristics associated with viral infections that are of concern to healthcare professionals include their highly infectious properties (eg HIV, SARS, etc.) and their h...

Claims

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Application Information

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IPC IPC(8): A01N43/58
CPCC07D401/14C07D401/12C07D413/10C07D471/04C07D413/14C07D405/14C07D401/10C07D405/10C07D491/052C07D401/06C07D491/048C07D405/12C07D487/04C07D491/10A61K38/212A61K31/4525A61K31/7056A61K45/06A61K31/454C07D401/04C07D405/04C07D491/107C07D513/04A61P1/00A61P1/02A61P1/16A61P11/00A61P13/08A61P15/00A61P25/00A61P27/16A61P3/00A61P31/00A61P31/10A61P31/12A61P31/14A61P31/20A61P31/22A61P35/00A61P35/02A61P3/06A61P43/00A61P5/14A61P3/10Y02A50/30A61K2300/00A61K31/4545A61K31/496A61K31/5377A61K31/55A61K31/437
Inventor 约翰·D·欧斯罗勃罗伯特·S·麦克道尔拉塞尔·约翰逊杨汉飚马克·伊万奇科克里斯蒂安那·A·泽哈利亚蔡海英莉莉·W·胡
Owner GANNEX PHARM CO LTD
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