Methods for treating disorders using nmda nr2b-subtype selective antagonist

A technology of disease and dosage, applied in the direction of anti-inflammatory agents, non-central analgesics, anti-tumor drugs, etc., can solve problems such as adverse side effects

Inactive Publication Date: 2011-02-16
EVOTECH INT GMBH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, clinical development of non-selective NMDA receptor antagonists is generally limited by unfavorable side effects, such as hallucinations

Method used

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  • Methods for treating disorders using nmda nr2b-subtype selective antagonist
  • Methods for treating disorders using nmda nr2b-subtype selective antagonist
  • Methods for treating disorders using nmda nr2b-subtype selective antagonist

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0029] A double-blind, placebo-controlled, randomized, single and multiple oral dose study was conducted to determine the safety and tolerability of the dihydrochloride salt of the compound of formula (I) in healthy young and elderly subjects. Conduct research in two parts.

[0030] Part 1 comprised an incremental single-dose, sequential group study in 48 young male subjects incorporated into a two-period crossover arm to investigate the effect of food. Part 2 comprised an incremental multiple-dose, sequential group study in 24 young male subjects and an incremental single- and multiple-dose, sequential group study in 18 elderly subjects (10 males and 8 females) . On each dosing occasion, subjects received a single capsule containing an appropriate amount of the dihydrochloride salt of the compound of formula (I) or microcrystalline cellulose. The treatment was administered orally with 240 ml of water while the subject was in an upright position.

[0031] The condition of e...

Embodiment 2

[0037] A double-blind, placebo-controlled study was performed in 19 healthy volunteers to investigate the effects of selective antagonism of the NMDA receptor NR2B subunit on cognitive function and neurophysiology, as measured by magnetic resonance imaging (MRI). This study utilized functional MRI to measure regional cerebral blood flow (rCBF) changes and putative modulation of neural networks during cognitive tasks performed by subjects administered the dihydrochloride salt of the compound of formula (I).

[0038] experimental method

[0039] Nineteen healthy male volunteers participating in this study were scanned using functional magnetic resonance imaging (fMRI) while performing cognitive tasks (including the PAL task described in more detail below) designed to measure associative learning, sustained attention, and episodic memory. These tasks were repeated on three study days, followed by fMRI sessions 2 hours later. On these three different occasions, participants rece...

Embodiment 3

[0069] The use of CSF sampling in drug development to assess drug or disease response has shown increasing relevance. CSF sampling values ​​for assessing central drug penetration and measuring bioactive substances have been consistently recognized. In general, CSF biomarkers enable therapeutic candidates to be examined more efficiently, exposing fewer people to ineffective drugs and doses, and accelerating the identification of effective therapies.

[0070] Lumbar puncture (LP) (as in intrathecal delivery of anesthetics, analgesics and chemotherapy) is routinely performed in a variety of clinical settings in diagnosis and treatment (Roos (2003) Lumbar puncture. Semin. Neurol. 23( 1): 105-14). Cerebrospinal fluid is produced by the ventricles (mainly the lateral ventricles) at a rate of 500ml / day. Since the volume that can be contained by the brain is of the order of 150 ml, it is often replaced (3-4 times a day with a turnover) and the excess enters the blood. This continuo...

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PUM

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Abstract

A method of treating, preventing or ameliorating a disease or condition by inhibiting NR2B subunit containing NMDA receptors using a compound according to formula (I) or a pharmaceutically acceptable salt thereof.

Description

Background of the invention [0001] Over the past two decades, extensive research has pointed to the important role of NMDA receptors in Alzheimer's disease (AD), Parkinson's disease, and pain perception . However, clinical development of non-selective NMDA receptor antagonists has generally been limited by adverse side effects, such as hallucinations. [0002] In the early 1990's, it was discovered that there are multiple NMDA receptor subtypes that contain different NR2(A-D) subunits. Receptors containing NR2B subunits have been implicated in the regulation of functions such as learning, memory processing, attention, emotion, mood, and pain perception, and in many human disorders. [0003] Compounds that selectively target NMDA receptors containing NR2B subunits are generally known. For example, US Patent No. 7,005,432 discloses a wide variety of substituted imidazol-pyridazine derivatives that are NMDA receptor subtype selective blockers that are said to be useful in the ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/505A61P25/28C07D403/06A61P25/16
CPCA61K31/505C07D403/06A61P25/00A61P25/04A61P25/16A61P25/18A61P25/24A61P25/28A61P25/30A61P29/00A61P35/00A61P43/00
Inventor 约翰·A·肯普蒂莫西·塔斯克
Owner EVOTECH INT GMBH
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