Heterocyclic modulators of lipid synthesis

A compound, cycloalkyl technology, applied in the field of heterocyclic regulators of lipid synthesis, which can solve the problems of side effects, hematopoietic and intestinal epithelial cell destruction, lack of improvement in cancer survival rate, etc.

Pending Publication Date: 2017-12-01
3 V BIOSCI INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The continued superiority of these long-established therapies is reflected in the lack of improvement in survival for most cancers
In addition to limited clinical success, classic therapies are associated with devastating s

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

[1289] Example 1 - FASN Inhibition by Compounds of the Disclosure

[1290] Determination of FASN biochemical activity: FASN enzyme was isolated from SKBr3 cells. SKBr3 is a human breast cancer cell line with high levels of FASN expression. It is estimated that FASN comprises approximately 25% of the cytosolic protein in this cell line. SKBr3 cells were homogenized in a Dunes homogenizer and then centrifuged at 4°C for 15 min 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 Western blot analysis. A similar method of isolating FASN from SKBr3 cells is described in Teresa, P. et al. (Clin. Cancer Res., 2009; 15(24), 7608-7615).

[1291] 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-di...

Embodiment 2

[1292] Example 2 - Antiviral Activity

[1293] Antiviral activity of Formulas (I-Z) was assessed using the HCV1b replicon system:

[1294]

[1295]The ET (luc-ubi-neo / ET) cell line, the Huh7 human hepatoma cell line carrying a stable luciferase (Luc) reporter gene and three cell culture-adaptive mutations in the HCV replicon, was used to construct the replicon (Pietschmann et al. , (2002) "Journal of Virology (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 as a positive control compound in each run. Subconfluent cultures of the ET line were seeded into 96-well plates dedicated to analysis of cell number (cytotoxicity) or antiviral activity, and the next day drugs were added to the appropriate wells. Cells were processed 72 hours later when they were still subconfluent. Determination of EC 50 (Concentrations that inhibit the replicon by 5...

Embodiment 3

[1298] Example 3 - FASN Inhibition Correlates with HCV Inhibition

[1299] The antiviral activity of 15 compounds of the present disclosure (numbered in relation to the compounds in Table 1) was measured using the HCV replicon system. According to published method (Lohmann et al., (1999) " Science (Science) ", 285 (5424): 110-113; Lohmann et al., (2001) " Journal of Virology (J.Virol.) ", 75 (3): 1437-1449; and Qi et al., (2009) Antiviral Res., 81(2):166-173), using Huh7 selected by G418, to establish the replicon cell line 1b (HCV1b / Luc- Neo replicon (1b Con1 with firefly gene integrated)). Replicon assembly using synthetic gene fragments. The GT1b line has PV-EKT and carries 3 adaptive mutations E1202G(NS3), T1280I(NS3), K1846T(NS4B), and the backbone is Con1. The medium is:

[1300] a) DMEM supplemented with 10% FBS, G418 (250 μg / ml), streptomycin (100 μg / ml) / penicillin (100 U / ml), L-glutamine (100×), NEAA (100×)

[1301] b) Medium prepared as follows:

[1302] i) 5...

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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 the benefit of and priority to US Provisional Application No. 62 / 135,631, filed March 19, 2015, the entire contents of which are hereby incorporated by reference. technical field [0003] The present disclosure generally relates to heterocyclic modulators of lipid synthesis and methods of use thereof. The heterocyclic modulators of lipid synthesis of the present disclosure can be used to treat disorders characterized by dysfunctional fatty acid synthase in a subject by modulating the fatty acid synthase pathway and / or fatty acid synthase function. Background technique [0004] Viral diseases are major health problems that threaten large numbers of people. Some of the characteristics associated with viral infections that are of concern to healthcare professionals include their high contagiousness (i.e. HIV, SARS, etc.) and high mutation potential. Some viruses are also oncogenic (eg HPV, EBV and HBV). Although vi...

Claims

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Application Information

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IPC IPC(8): C07D401/12C07D407/12C07D471/04C07D487/04C07D211/34A61K31/454A61P35/00A61P31/12
CPCC07D211/34C07D401/12C07D407/12C07D471/04C07D487/04A61K31/451A61K31/4525A61K31/454A61K31/4545A61K31/5377A61K31/55C07D401/10C07D405/12A61P1/16A61P11/00A61P31/12A61P31/16A61P31/18A61P35/00A61P35/02A61P43/00A61K45/06
Inventor J·D·奥斯洛布R·S·麦克道尔R·约翰逊H·杨M·伊万奇克C·A·扎哈里亚H·蔡L·W·胡G·杜克Y·欧豪T·S·霍耶尔M·奥法雷
Owner 3 V BIOSCI INC
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