Use of 2-phenyl-6-(1h-imidazol-1-yl)quinazoline for treating neurodegenerative diseases, preferably alzheimer's disease

A neurodegenerative, quinazoline technology for neurological diseases, antiviral agents, organic active ingredients, etc., that can address issues such as failure to reach primary endpoints

Pending Publication Date: 2021-12-17
ROTTAPHARM BIOTECH SRL
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Sadly, in May 2017, it was announced that this approach using PKCε bryostatin-1 failed to meet the primary endpoint measured by the Severe Impairment Scale (SIB) in a phase II proof of concept study Improvement in Scores Relative to Placebo

Method used

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  • Use of 2-phenyl-6-(1h-imidazol-1-yl)quinazoline for treating neurodegenerative diseases, preferably alzheimer's disease
  • Use of 2-phenyl-6-(1h-imidazol-1-yl)quinazoline for treating neurodegenerative diseases, preferably alzheimer's disease
  • Use of 2-phenyl-6-(1h-imidazol-1-yl)quinazoline for treating neurodegenerative diseases, preferably alzheimer's disease

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0064] Example 1: Effect of 2-phenyl-6-(1H-imidazol-1-yl)quinazoline on inflammatory gene expression in vitro

[0065] method

[0066] These experiments used astrocytes, a human glioblastoma astrocytoma cell line U373 MG (Uppsala) model. in DMEM supplemented with 10% FBS at 37 °C and CO 2 Next, culture adherent cells. 72 h after plating, cells were treated with 2-phenyl-6-(1H-imidazol-1-yl)quinazoline (CR4056) (10 μM) prepared according to EP2066653 for 1 h, followed by the pro-inflammatory cytokine IL-1β (2ng / mL) stimulation for 6 and 24h.

[0067] At the end of the incubation period, total RNA was obtained and reverse transcribed using the High Capacity cDNA Reverse Transcription Kit (Thermo Fisher Scientific). The expression levels of COX-2, IL-1β, IL-6 and TNFα were assessed by RT-PCR analysis using the Applied Biosystems 7500 Fast Real-Time PCR System (Applied Biosystems 7500 Fast Real-Time PCRSystem), using specific TaqMan assays, as Endogenous control, use 18S pre-...

Embodiment 2

[0076] Example 2: In vitro effect of 2-phenyl-6-(1H-imidazol-1-yl)quinazoline (CR4056) on the translocation of PKCε to the plasma membrane in cultured neurons

[0077] method

[0078] Rat dorsal root ganglia (DRG) were obtained from freshly isolated spinous processes after careful removal of the nerve trunk and connective tissue. Larger ganglia were cut into 2-4 small pieces and incubated in 0.125% collagenase (Worthington, Freehold, NJ) in Dulbecco's Modified Eagle's Medium (DMEM) at 37°C For 1 hour, the medium contained 10% fetal bovine serum (FBS) plus 1% penicillin / streptomycin and 1% L-glutamine (Euroclone, Milan, Italy). After enzymatic digestion, ganglia were mechanically dissociated and placed in Petri dishes containing wells with glass-bottom coverslips (pre-coated with 10 μg / mL poly-L-lysine (poly-L-lysine) and 20 μg / ml laminin, Sigma Aldrich, Milan, Italy), neurons were plated at a density such that neurons covered about 30% of the coverslip surface in a single la...

Embodiment 3

[0084] Example 3: In vivo effect of 2-phenyl-6-(1H-imidazol-1-yl)quinazoline (CR4056) on microglial activation in the CFA inflammation model

[0085] method

[0086] Microglial activation was assessed by immunofluorescence staining, and in the complete Freund's adjuvant (CFA) model, the expression of ionized calcium-binding adapter molecule 1 (Iba-1) was measured in the ipsilateral L5 spinal cord.

[0087] Induce unilateral inflammation by injecting 100 μL of CFA (1 mg / mL, diluted 1:1 with saline) into the phalanx of the rat's right hind paw.

[0088]At 72 hours after CFA, CR4056 (6 mg / kg, os) was administered, and 90 minutes later, the animal was deeply anesthetized with excess urethane (1.5 g·kg-1, i.p.), and then transcardially perfused with 250 mL of 0.9% 1 % heparin in saline (5000 UI·mL-1 ), followed by 500 mL of 10% formalin (ie 4% paraformaldehyde, Bio-Optica Spa, Milan, Italy). Spinal cord L5 segments were harvested, fixed overnight at 4°C, and embedded in paraffin ...

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PUM

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Abstract

The invention concerns a compound of formula 2-phenyl-6-(1H-imidazol-1-yl)quinazoline or a pharmaceutically acceptable salt thereof for use in the treatment of a neurodegenerative disease. The neurodegenerative disease is a disease selected from the group consisting of Alzheimer's disease, Lewy body dementia, frontotemporal dementia, amyotrophic lateral sclerosis, Huntington disease, prion diseases, HIV-associated dementia and any form of cognitive disorders linked to neurodegeneration, preferably Alzheimer's disease.

Description

technical field [0001] The present invention provides 2-phenyl-6-(1H-imidazol-1-yl)quinazolines for the treatment of neurodegenerative diseases, preferably Alzheimer's disease. Background technique [0002] Neurodegenerative diseases (NDs) are a cause of increasing mortality and morbidity worldwide, especially among the elderly. They encompass highly diffuse pathologies such as Alzheimer's disease, Parkinson's disease, dementia with Lewy bodies, frontotemporal dementia, amyotrophic lateral sclerosis, Huntington's disease, and prion diseases, with particular focus on the linkages between these syndromes. similarities and differences. [0003] Neurodegenerative diseases pose great challenges to basic science and clinical medicine due to their ubiquity, complex biochemical and pathological characteristics. [0004] Novel mechanisms of related therapy therefore represent an unmet medical need. [0005] Alzheimer's disease (AD) is the most common type of dementia associated wi...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/517A61P25/28A61P25/00A61P25/14A61P31/12
CPCA61K31/517A61P25/28A61P25/00A61P25/14A61P31/12A61K45/06A61P25/16
Inventor L·C·罗瓦蒂G·卡塞利E·萨拉
Owner ROTTAPHARM BIOTECH SRL
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