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Method of treatment with histamine-3 receptor inverse agonist

An inverse agonist, histamine technology, applied in the field of quantitative histamine-3, can solve the problems of reduced quality of life of narcolepsy individuals

Pending Publication Date: 2021-02-12
SUVEN LIFE SCI LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

These symptoms of narcolepsy result in a significantly reduced quality of life for individuals with narcolepsy

Method used

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  • Method of treatment with histamine-3 receptor inverse agonist
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  • Method of treatment with histamine-3 receptor inverse agonist

Examples

Experimental program
Comparison scheme
Effect test

Embodiment approach

[0063] The present invention encompasses, but is not limited to, all of the embodiments described herein, however, some preferred aspects and elements of the invention are discussed herein in the form of the following embodiments.

[0064] In one embodiment, the invention relates to the treatment of narcolepsy, excessive daytime sleepiness, obstructive sleep apnea, circadian rhythm sleep disorder, associated with Parkinson's disease, multiple sclerosis, dementia or attention deficit hyperactivity disorder A method of sleep and alertness disorders comprising administering to a patient in need thereof a therapeutically effective amount of a histamine-3 receptor inverse agonist, wherein the histamine-3 receptor inverse agonist is N-[4- (1-cyclobutylpiperidin-4-yloxy)phenyl]-2-(morpholin-4-yl)acetamide or a pharmaceutically acceptable salt thereof.

[0065] In another embodiment, the present invention is directed to a method of treating narcolepsy comprising administering to a pat...

Embodiment 1

[0178] Example 1: K in the context of human and rat histamine-3 receptors i Determination of value:

[0179] Histamine-3 membranes were prepared from recombinant CHO-k1 cells expressing human histamine-3 receptor or rat histamine-3 receptor. Radioligand (RS)-[alpha]-methylhistamine [cyclo-1,2-3H] was purchased from American Radiolabeled chemicals (ARC) (Catalog No. ART 1342). Final ligand concentration was 3 nM; non-specific determinants were methylhistamine (100 μM) and histamine-3 membrane (60 μg / well). Methylhistamine was used as a positive control. at 25°C in a solution containing 5 mM MgCl 2 The reaction was carried out in a binding buffer of 50 mM Tris-HCl (pH 7.4) for 60 minutes. The incubation was terminated by rapid filtration, followed by washing the binding mixture 4 times using 96-well harvest plates (Millipore, cat# MSFCNXB50) pre-coated with 0.5% polyethyleneimine. Plates were dried and bound radioactivity collected on the filters was determined by scintilla...

Embodiment 2

[0183] Example 2: IC in the context of the human histamine-3 receptor 50 Determination of value:

[0184] Compounds were tested under Eurofins Cerep Panlabs according to the following procedure.

[0185] Materials and methods:

[0186] Source of receptor: human recombinant expressed in CHO-K1 cells

[0187] Radioligand: [35S]-GTPγS

[0188] Vehicle: 1% DMSO

[0189] Reference agonist: R(-)-α-methylhistamine

[0190] Agonist concentration: 30nM

[0191] Positive control: Thioperamide

[0192] Incubation conditions: at 30°C in a medium containing 100mM NaCl, 10mM MgCl 2 , 1 mM DTT, 1 mM EDTA in 20 mM HEPES (pH 7.4) for 30 minutes. After incubation, scintillation is measured on a luminescence counter and compared to control values ​​in order to determine any interaction of the test compound with the cloned histamine-3 binding site.

[0193] result:

[0194] The compound SUVN-G3031 exhibits the functional properties of an inverse agonist. IC 50 The values ​​are tabulat...

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Abstract

The present invention provides new methods of treatment for narcolepsy, excessive daytime sleepiness, obstructive sleep apnea, circadian rhythm sleep disorders, sleep and vigilance disorders associated with Parkinson's disease, multiple sclerosis, dementia or attention deficit hyperactivity disorder by administering a therapeutically effect amount of histamine-3 receptor (H3R) inverse agonist, N-[4-(l-Cyclobutylpiperidin-4-yloxy)phenyl]- 2-(morpholin-4-yl)acetamide or a pharmaceutically acceptable salt thereof. The present invention further provides use of the said compounds in the manufactureof medicament intended for the treatment of the disorders described herein.

Description

technical field [0001] The present invention provides a therapeutically effective dose of histamine-3 receptor (histamine-3 receptor, H 3 R) inverse agonist N-[4-(1-cyclobutylpiperidin-4-yloxy)phenyl]-2-(morpholin-4-yl)acetamide or a pharmaceutically acceptable salt thereof for treatment Narcolepsy, excessive daytime sleepiness, obstructive sleep apnea, circadian rhythm sleep disorder, and Parkinson's disease, multiple sclerosis, dementia, or attention deficit hyperactivity disorder A new approach to sleep and vigilance disorders associated with hyperactivity disorders. The invention also provides the use of said compounds in the manufacture of a medicament intended for the treatment of the disorders described herein. Background technique [0002] Narcolepsy is a chronic neurological disorder involving a reduced ability to regulate the sleep-wake cycle and is characterized by excessive daytime sleepiness and abnormal rapid eye movement (REM) sleep manifestations, including...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/5377A61P25/00
CPCA61K31/5377A61P25/00
Inventor 罗摩克里希纳·尼罗吉阿尼尔·卡巴里·欣德维贾伊·西德拉姆·贝纳德萨伊维沙尔·达里佩利普拉迪普·贾亚拉扬乔茨纳·拉武拉文卡特斯瓦卢·贾斯蒂
Owner SUVEN LIFE SCI LTD
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