Compounds for use in the treatment of brain diseases

A brain tumor and compound technology, applied in the field of compounds used in brain tumor treatment, can solve problems such as obstacles and achieve the effect of increasing the drug delivery rate

Pending Publication Date: 2020-11-27
UNIV DEGLI STUDI DI ROMA LA SAPIENZA +2
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0012] GlaB acts by hindering the interaction between the transcription factor Gli1 and DNA, thus inhibiting the transcriptional activity of factors belonging to the Gli protein family

Method used

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  • Compounds for use in the treatment of brain diseases
  • Compounds for use in the treatment of brain diseases
  • Compounds for use in the treatment of brain diseases

Examples

Experimental program
Comparison scheme
Effect test

preparation example Construction

[0092] Preparation of GlaB / PEG-cholane formulation

[0093] GlaB can be synthesized as described in Delle Monache, F. et al. (1977), Italian Journal of Chemistry 107(7-8): 403-407 and WO 2014 / 207069 Al.

[0094] PEG-cholane can be synthesized as follows: Salmaso, S. et al. "Self-assembled nanocomposites for protein delivery: supramolecular interactions between PEG-cholane and rh-G-CSF (Self- -assembling nanocomposites for protein delivery: Supramolecular interactions between PEG-cholane and rh-G-CSF)", Journal of Controlled Release (Journal of Controlled Release) 162, 176-184 (2012), and Ambrosio, E. et al. A novel combined strategy for the physical PEGylation of polypeptides", Journal of Controlled Release 226, 35-46 (2016).

[0095] A 1 mL volume of GlaB solution (2.0 mg / mL, 4.4 mM) in methanol was added to 1 mL of PEG in methanol at various concentrations 5kDa - in cholane solution. Methanol was removed under reduced pressure and 1 mL of 10 mM phosphate, 0.15 M NaCl, pH ...

Embodiment 1

[0126] Example 1: Treatment with Compounds of the Invention Reduces Glioma Growth in Vitro

[0127] figure 1 The experimental data in showed that the growth capacity of GL261 murine glioma cells treated with 5 μM GlaB was reduced compared to the same cells treated with vehicle only (DMSO). The treatment was effective between 24 and 48 hours, around the time of the first attempt at tumor cell replication, which relies in part on activation of the Hedgehog signaling pathway.

Embodiment 2

[0128] Example 2: Treatment with Compounds of the Invention Reduces Glioma Growth in Vivo

[0129] figure 2 The experimental data in shows that compared with the volume measured in the mice treated with the control solution (ethanol:2-hydroxypropyl-β-cyclodextrin solution, 1:5v:v), at 4.4mg / kg and The intranasal and intraperitoneal administration of GlaB at a concentration of 35 mg / kg can significantly reduce the volume of glioma in vivo ( figure 2 ). Furthermore, intranasal administration was unexpectedly effective at concentrations approximately 8-fold lower than intraperitoneal concentrations.

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Abstract

The present invention relates to a compound of formula (1): (1) or an analogue thereof or a pharmaceutically acceptable salt thereof, for use in the treatment of a brain tumor, wherein said compound is administered intranasally and relative pharmaceutical compositions.

Description

technical field [0001] The present invention relates to a method for rapidly and efficiently distributing a compound of formula (I), its analogue or a pharmaceutically acceptable salt thereof used alone or together with other compounds, and related pharmaceutical compositions: [0002] [0003] Specifically, these compounds achieve systemic circulation by intranasal administration. Rapid onset of beneficial effects of rapid treatment and / or prevention of brain tumors is then achieved. Background technique [0004] Glioblastoma is the most widespread and aggressive tumor of the central nervous system (CNS), characterized by high levels of tumor cell invasion and proliferation, and high levels of inflammation and necrosis of nervous tissue (1). Although neurosurgery and the development of new drugs are ongoing, there are currently no effective treatments against the growth of this brain tumor, and patient death occurs within approximately twelve months of pathological diag...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/366A61K45/06A61P35/00A61K9/00A61K9/16A61K9/20A61K47/60
CPCA61K9/0043A61K45/06A61K9/1641A61K9/2031A61K31/366A61P35/00A61P35/04A61K9/08A61K47/40
Inventor C·立马托拉G·达勒桑德罗L·迪马克图里欧P·因芳特B·博特M·莫里F·吉尔咖C·因戈尔莉娜S·波拉多兹P·卡力册提S·萨尔马索M·德马蒂诺F·加司帕里尼D·瓜格里欧
Owner UNIV DEGLI STUDI DI ROMA LA SAPIENZA
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