Quinazoline scaffold based compounds, pharmaceutical compositions and methods of use thereof

一种化合物、组合物的技术，应用在杂环化合物领域，能够解决ΔΨm塌陷等问题，达到预防细胞死亡的效果

Active Publication Date: 2017-02-22
TECHNION RES & DEV FOUND LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The opening of VDAC can cause the collapse of ΔΨm

Method used

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  • Quinazoline scaffold based compounds, pharmaceutical compositions and methods of use thereof
  • Quinazoline scaffold based compounds, pharmaceutical compositions and methods of use thereof
  • Quinazoline scaffold based compounds, pharmaceutical compositions and methods of use thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0169] Example 1 - Materials and Methods for Bioassays

[0170] TSPO Binding and Western Blot Protein Analysis The TSPO binding assay was used to determine whether compounds of the invention were able to compete with standard TSPO ligands according to previously described methods (Veenman et al., 2004; Levin et al., 2005) and used as mass control. Briefly, the assay utilizes a radioactive standard ligand [ 3 H] PK 11195 (1-(2-chlorophenyl)-N-methyl N-(1-methyl-propyl)-3 isoquinoline carboxamide), and measure the compound of the present invention to replace the standard ligand binding TSPO capabilities. Total radioactivity incorporation was determined by measuring the radioactivity of the radioligand-receptor complex obtained in the reaction of radioactive standards with TSPO. Radioactive standards and checked compounds are added to TSPO and after an incubation time the radioactivity of the resulting ligand-receptor complexes is measured with the aid of a gamma-counter. T...

Embodiment 2

[0176] Example 2 - Binding of TSPO in vitro

[0177] As described above, using the [ 3 H] PK 11195 radioassay to assess binding to TSPO.

[0178] In Table 1 the results for the binding and protection of compounds of the invention against TSPO are provided. Compounds 1-8 were tested in cell culture and the superior compound (ie Compound 1) was also tested in animal models. The structures of these compounds are provided above. Table 1 also includes the compound covered by US 8,541,428 (compound A).

[0179] Table 1

[0180] compound Ki(nM) Protect* 1 ≈60 excellent 2 ≈380 it is good 3 ≈1506 it is good 4 ≈45 it is good 5 ≈600 excellent 6 ≈60 excellent 7 ≈2.5 it is good 8 ≈2.5 it is good A ≈600 it is good

[0181] * Prevents glutamate-induced cell death

[0182]

[0183] Comparison of Compound 1 of the present invention with Compound A, which is exemplified in US 8,541,428, indicates that ...

Embodiment 3

[0186] Example 3: Protective properties of compounds of the invention

[0187] Compounds of the present invention prevent U118MG cells of astrocyte origin (Figures 1, 2, 3 and 8) or SH SY 6Y cells of neuron origin ( Figure 4 ) cell death induced by glutamate in cell culture. Figure 1 shows that compound 1, which has a good affinity for TSPO (Table 1), prevents glutamate-induced cell death and cell death process. Such as Figure 1A As shown in , compound 1 of the present invention prevented glial cell death induced by 35 mM glutamate in cell culture (results are plotted as AVG±SD). In the control group, 35 mM glutamate killed -60% of the cells. Compound 1 significantly prevented glutamate-induced cell death in glial cell cultures at concentrations of 10-100 μM. In contrast, prior art Compound A (US Pat. No. 8,541,428) was surprisingly significantly less effective at preventing cell death ( Figure 8A ). For each group, *p<0.05 versus glutamate exposure (glu), ***p<0.001...

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PUM

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Abstract

The present invention relates to novel heterocyclic compounds based on a quinazoline scaffold of formula (I), which bind effectively to the mitochondrial translocator protein (TSPO), and counteract cell death processes. These compounds can also stimulate neuronal differentiation. The present invention further relates to pharmaceutical compositions including such compounds, and methods of using these compounds for the prevention and treatment of brain damage resulting from brain injury, especially secondary brain damage due to traumatic brain injury (TBI). The compounds of the invention are also useful in preventing, treating, and curing brain damage due to neurodegenerative diseases, including underlying and associated pathological and mental disorders. The compounds can also be used to prevent and treat brain damage due to infection, toxic challenges, and excessive drug use, e.g., recreational, over the counter, or prescription drugs. These compounds can also prevent heart failure, for example associated with brain injuries and brain diseases.

Description

technical field [0001] The present invention relates to heterocyclic compounds based on quinazoline scaffolds that efficiently bind to mitochondrial translocator protein (TSPO) and resist cell death processes. The invention further provides pharmaceutical compositions comprising such compositions, as well as methods of using these compounds, particularly for the treatment and prevention of neurodegenerative diseases and neurodegenerative diseases due to acute events such as traumatic brain injury (TBI) or their sequelae. ) or chronic aggression (eg, infection, toxin, or drug use)—including the underlying pathological process—induced brain injury. Background technique [0002] Neurodegeneration due to neurodegenerative brain diseases and injuries is a major health and economic concern. Current models predict that the total number of people with Alzheimer's disease will at least triple between 2000 and 2050. The widely accepted view that the underlying cause of neurodegenera...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D239/91A61K31/517A61P25/00A61P9/10A61P31/00A61P31/12A61P7/10A61P25/28A61P25/16A61P25/14A61P37/06A61P25/20A61P3/00A61P3/10A61P25/18A61P27/16A61P9/04
CPCC07D239/91A61P25/00A61P25/02A61P25/14A61P25/16A61P25/18A61P25/20A61P25/28A61P27/16A61P3/00A61P31/00A61P31/04A61P31/12A61P33/02A61P37/06A61P7/10A61P9/00A61P9/04A61P9/10A61P3/10
Inventor M·加维什J·A·卫嫚A·斯特人博格I·马雷克A·魏因施泰因A·阿维塔勒
Owner TECHNION RES & DEV FOUND LTD
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