Ethyl (2R)-2-acetamido-3-(4-methylbenzoylsulfanyl)propanoate and uses thereof

a technology of ethyl (2r)-2 acetamido and propanoate, which is applied in the field of new substituted nacetyllcysteine (“ nac”) derivatives, can solve the problems of low brain penetration, limited treatment and effective effect, and cell death

Active Publication Date: 2015-05-14
PROMENTIS PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

); however, this treatment is limited to and effective with only a small adrenoleukodystrophy subpopulation, with success typically coming when it is performed in the early stages of the disease.
Subsequently, very-long chain fatty acids build up in affected cells, leading to oxidative stress and eventually metabolic failure resulting in cell death, features common to human patients and animal models (Fourcade, S, et al.
However, brain penetrance is low and the long-term risks and benefits remain unknown.
Inherited mitochondrial diseases (e.g. Leigh syndrome, Alpers' disease, and MELAS) affecting the CNS are highly variable, and often result in the progressive loss, or dysfunction, of neurons or neuroglial cells.
In addition, impaired cystine-glutamate antiporter activity and faulty glutamate neurotransmission bear on the issue of uncontrolled drug use, i.e., drug addiction.
NAC undergoes extensive first pass metabolism requiring the usage of high doses that limit the utility of the drug and, potentially, increase the chances of side effects due to the buildup of metabolized by-products.
In addition, NAC demonstrates poor CNS penetration due to an inability to cross the blood brain barrier.

Method used

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  • Ethyl (2R)-2-acetamido-3-(4-methylbenzoylsulfanyl)propanoate and uses thereof
  • Ethyl (2R)-2-acetamido-3-(4-methylbenzoylsulfanyl)propanoate and uses thereof
  • Ethyl (2R)-2-acetamido-3-(4-methylbenzoylsulfanyl)propanoate and uses thereof

Examples

Experimental program
Comparison scheme
Effect test

example 1

Synthesis Strategies

[0070]General Methods

[0071]1H-NMR spectra were obtained on a Varian Mercury 300-MHz NMR. Purity (%) was determined with a Waters Alliance 2695 HPLC (Waters Symmetry C18, 4.6×75 mm, 3.5 □m) with a 2996 diode array detector from 210-400 nm.

Synthesis of Ethyl (2R)-2-acetamido-3-(4-methylbenzoylsulfanyl)propanoate (Pro-4051)

[0072]

2-Acetylamino-3-(4-methyl-benzoylsulfanyl)-propionic acid

[0073]To a solution of benzotriazole (9.91 g, 83.2 mmol) in tetrahydrofuran (80 mL) was added 4-methylbenzoyl chloride (5.0 mL, 37.8 mmol) (5 g, 95%). After 2 hours, the resulting slurry was filtered and the solid was rinsed with tetrahydrofuran (25 mL). The filtrates were combined and added to a solution of N-acetyl-L-cysteine (5.55 g, 34.0 mmol) and N-methylmorpholine (3.74 mL, 34.0 mmol) in tetrahydrofuran (50 mL) at 0° C. The resulting mixture was allowed to warm to ambient temperature over 16 hours. Aqueous hydrochloric acid (1 M, 100 mL) was added to the mixture and the resulting...

example 2

In Vitro Studies

[0075]14C Uptake by Pro-4051

[0076]The goal of these experiments was to determine 14C-cystine uptake. The experiments were conducted as follows.

[0077]The screening of the compound was performed using an in vitro culture system of human glial cells from brain astrocytoma (1321N1). Cells were plated on 24 well plates coated with poly-D-lysine and laminin and grown in a balanced salt solution supplemented with 5% heat inactivated horse serum, 5% fetal bovine serum, 2 mM glutamine and glucose (total 21 mM). Cultures were maintained in humidified 5% CO2 incubators at 37° C. for 3-4 days before experiments were performed, at this time the cultures has formed a single confluent layer. For experiments, cultures were washed 3 times into a Na-free HEPES and HCO3− buffered balanced salt solution. After 1 hour the test compounds are added. Following a three hour incubation, 14C-cystine (0.025 mCi / mL) was then added for 20 minutes. Following the 14C-cystine exposure, cultures were...

example 4

In Vivo Studies

[0088]Prepulse Inhibition Experiment

[0089]The goal of this experiment was to demonstrate the efficacy of the test compounds in a predictive animal model of schizophrenia.

[0090]The experiment was conducted as follows.

[0091]Rats were placed on a platform in a sound attenuating chamber (10.875″×14″×19.5″; Hamilton Kinder, CA) that rested on a motion sensing plate. During all sessions, the background noise was held constant at 60 dB. A matching session was conducted to determine the magnitude of the average startle response for each rat. This session consisted of a five minute habituation period followed by 20 trials; 17 trials involved the presentation of a single auditory stimulus (pulse stimulus; 50 dB above the background noise) and three trials in which a pre-pulse stimulus (12 db above background) was presented 100 ms before the pulse auditory stimulus. Rats were then assigned into the various treatment groups so that the magnitude of the startle response was equiva...

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Abstract

A novel substituted N-acetyl-L-cysteine (NAC) derivative and methods of using this compound for the treatment of diseases and / or conditions, including but not limited to diseases and / or conditions of, or involving, the Central Nervous System (CNS), including schizophrenia adrenoleukodystrophy, mitochondrial diseases (e.g. Leigh syndrome, Alpers' disease, and MELAS), Huntington's disease, trichotillomania, HIV-associated neurocognitive disorder, hypoxic-ischemic encephalopathy, drug craving, and drug addiction.

Description

FIELD OF THE INVENTION[0001]This invention relates to a novel substituted N-acetyl-L-cysteine (“NAC”) derivative and methods of using this compound for the treatment of diseases and / or conditions, including but not limited to diseases and / or conditions of or involving, the Central Nervous System (CNS), including schizophrenia adrenoleukodystrophy, mitochondrial diseases (e.g. Leigh syndrome, Alpers' disease, and MELAS), Huntington's disease, trichotillomania, HIV-associated neurocognitive disorder, hypoxic-ischemic encephalopathy, drug craving, and drug addiction.BACKGROUND OF THE INVENTION[0002]Schizophrenia is a debilitating disorder afflicting 1% of the world's population. The development of effective medications to treat schizophrenia relies on advances in characterizing the underlying pathophysiology. Chlorpromazine and other phenothiazines are considered first generation antipsychotics (termed “typical antipsychotics”) useful in the treatment of schizophrenia.[0003]Adrenoleuko...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): C07C327/34
CPCC07C327/34C07D327/04C07D241/08C07C323/57C07C323/60A61K31/265C07C323/58C07C323/59C07C329/06C07D277/14A61K31/165A61K31/426A61K31/513C07D277/08A61P25/00A61P25/14A61P25/18A61P25/28A61P25/30A61P43/00A61P9/10C07C327/32C07C327/26
Inventor NEARY, MICHAELNIEMAN, JAMESTANIS, STEVENLAWTON, DANIEL
Owner PROMENTIS PHARMA
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